Solid carriers for improved delivery of active ingredients in pharmaceutical compositions

ABSTRACT

The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides. The compositions of the present invention can be used for improved delivery of hydrophilic or hydrophobic pharmaceutical active ingredients, such as drugs, nutritional agents, cosmeceuticals and diagnostic agents.

This application is a continuation of U.S. patent application Ser. No.11/196,805, filed Aug. 2, 2005, which is a continuation-in-part of U.S.patent application Ser. No. 10/428,341, filed on May 1, 2003, now issuedas U.S. Pat. No. 6,923,988, which is a continuation of U.S. Ser. No.09/800,593 filed on Mar. 6, 2001, now issued as U.S. Pat. No. 6,569,463,which is a divisional of U.S. Ser. No. 09/447,690, filed on Nov. 23,1999, now issued as U.S. Pat. No. 6,248,363, each of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical delivery systems forpharmaceutical active ingredients, such as drugs, nutritionals,cosmeceuticals, and diagnostic agents. In particular, the presentinvention provides compositions and dosage forms including solidcarriers for improved delivery of pharmaceutical active ingredients.

BACKGROUND OF THE INVENTION

Hydrophobic active ingredients, such as progesterone, cyclosporin,itraconazole and glyburide present delivery challenges due to their pooraqueous solubility and slow dissolution rate. Several commercialproducts of these hydrophobic drugs are available, the various productsusing different methods to try to enhance in vivo performance. Oneapproach is size reduction by micronization, such as in Prometrium(micronized progesterone) and Micronase (micronized glyburide). Otherapproaches include size reduction in emulsion formulations, such as inSandimmune (cyclosporin emulsion) and NeOral (cyclosporinmicroemulsion). These approaches suffer from several disadvantages.Micronization/nanonization presents processing and stability challenges,as well as dissolution limitations, since the micronized/nanosized drugstill possesses a high degree of crystallinity. Liquid formulationspresent drug precipitation and packaging challenges, due to solventevaporation. Moreover, non-solid formulations are more prone to chemicalinstability and capsule shell incompatibility, leading to thepossibility of leakage upon storage.

For hydrophilic active ingredients, the formulation challenges aredifferent. Although these compounds are readily soluble in the aqueousgastrointestinal environment, they are poorly absorbed, due to poormembrane permeability and/or enzymatic degradation. Surfactants andlipophilic additives have been reported to improve membranepermeability; see, e.g., LeCluyse and Sutton, “In vitro models forselection of development candidates. Permeability studies to definemechanisms of absorption enhancement,” Advanced Drug Delivery Reviews,23, 163-183 (1997). However, these compositions fail to maintaineffective levels and type of enhancers for bioacceptable absorptionenhancement. Most solid dosage forms of hydrophilic active ingredientsexhibit poor or no absorption of the active. Moreover, these non-solidformulations suffer from the disadvantages of chemical instability,leakage and capsule shell incompatibility as discussed above.

Solid carriers for pharmaceutical active ingredients offer potentialadvantages over micronized drugs, emulsions or solubilized formulations.Solid carriers, typically of size less than about 2 mm, can easily passthrough the stomach, thus making the performance less prone to gastricemptying variability. Further, the problems of leakage and otherdisadvantages of liquid formulations are not present in solid carrierformulations. To date, however, such solid carrier formulationsgenerally have been limited to a few specific drugs, due to difficultiesin formulating appropriate drug/excipient compositions to effectivelycoat the active ingredient onto a carrier particle.

Conventional solid dosage forms of hydrophobic active ingredients, suchas tablets, or multiparticulates in capsules, often exhibit slow andincomplete dissolution and subsequent absorption. These formulationsoften show a high propensity for biovariability and food interactions ofthe active ingredient, resulting in restrictive compliance/labelingrequirements.

Due to the slow dissolution and dependence on gastric emptying, soliddosage forms often delay the onset of some hydrophobic activeingredients.

Thus, there is a need for pharmaceutical compositions and dosage forms,and methods therefor, that do not suffer from the foregoingdisadvantages.

SUMMARY OF THE INVENTION

It is an object of the invention to provide solid pharmaceuticalcompositions having active ingredients in a rapid dissolvable and moresolubilized state therein.

It is another object of the invention to provide solid pharmaceuticalcompositions having more rapid dissolution upon administration to apatient.

It is another object of the invention to provide solid pharmaceuticalcompositions having more sustained and complete solubilization uponadministration to a patient.

It is another object of the invention to provide solid pharmaceuticalcompositions capable of delivery a wide variety of pharmaceutical activeingredients.

It is another object of the invention to provide solid pharmaceuticalcompositions of coated substrate materials without the need for binders.

It is another object of the invention to provide solid pharmaceuticalcompositions having increased chemical stability of the activeingredient

It is another object of the invention to provide solid pharmaceuticalcompositions capable of improving the absorption and/or bioavailabilityof pharmaceutical active ingredients.

It is another object of the invention to provide solid pharmaceuticalcompositions having better protection of the upper gastrointestinaltract from untoward effects of the active ingredient.

It is another object of the present invention to provide solidpharmaceutical compositions capable of improving the palatability of ormasking the taste of unpalatable pharmaceutical active ingredients.

In accordance with these and other objects, the present inventionprovides solid pharmaceutical compositions for improved delivery of awide variety of pharmaceutical active ingredients contained therein orseparately administered.

In one embodiment, the solid pharmaceutical composition includes a solidcarrier, the solid carrier including a substrate and an encapsulationcoat on the substrate. The encapsulation coat includes at least oneionic or non-ionic hydrophilic surfactant. Optionally, the encapsulationcoat can include a pharmaceutical active ingredient, a lipophiliccomponent such as a lipophilic surfactant or a triglyceride, or both apharmaceutical active ingredient and a lipophilic component.

In another embodiment, the solid pharmaceutical composition includes asolid carder, the solid carrier including a substrate and anencapsulation coat on the substrate. The encapsulation coat includes alipophilic component, such as a lipophilic surfactant or a triglyceride.Optionally, the encapsulation coat can include a pharmaceutical activeingredient, an ionic or non-ionic hydrophilic surfactant, or both apharmaceutical active ingredient and a hydrophilic surfactant.

In another embodiment, the solid pharmaceutical composition includes asolid carrier, the solid carrier including a substrate and anencapsulation coat on the substrate. The encapsulation coat includes apharmaceutical active ingredient and an ionic or non-ionic hydrophilicsurfactant; a pharmaceutical active ingredient and a lipophiliccomponent such as a lipophilic surfactant or a triglyceride; or apharmaceutical active ingredient and both a hydrophilic surfactant and alipophilic component.

In another embodiment, the solid pharmaceutical composition includes asolid carrier, wherein the solid carrier is formed of at least twocomponents selected from the group consisting of pharmaceutical activeingredients; ionic or non-ionic hydrophilic surfactants; and lipophiliccomponents such as lipophilic surfactants and triglycerides.

In other aspects, the present invention also provides dosage forms ofany of the solid pharmaceutical compositions, and methods of using thesolid pharmaceutical compositions.

These and other objects and features of the present invention willbecome more fully apparent from the following description and appendedclaims, or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWING

In order to illustrate the manner in which the above-recited and otheradvantages and objects of the invention are obtained, a more particulardescription of the invention briefly described above will be rendered byreference to specific embodiments thereof which are illustrated in theappended drawings. Understanding that these drawings depict only typicalembodiments of the invention and are not therefore to be considered tobe limiting of its scope, the invention will be described and explainedwith additional specificity and detail through the use of theaccompanying drawings in which:

FIG. 1 is a graph showing the extent of dissolution/release of glyburideas a function of time for a composition according to the presentinvention and two prior art compositions.

FIG. 2A is a graph showing the extent of dissolution/release ofprogesterone as a function of time for two compositions according to thepresent invention and the pure bulk drug.

FIG. 2B is a graph showing the extent of dissolution/release ofprogesterone as a function of time for two compositions of the presentinvention, a conventional commercial formulation of progesterone, andthe pure bulk drug.

FIG. 3 is a graph showing the extent of dissolution/release ofomeprazole as a function of time for two compositions according to thepresent invention and a prior art composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides solid pharmaceutical compositions forimproved delivery of a wide variety of pharmaceutical activeingredients, contained therein or separately administered. In oneembodiment, the solid pharmaceutical composition includes a solidcarrier, the solid carrier including a substrate and an encapsulationcoat on the substrate. The encapsulation coat can include differentcombinations of pharmaceutical active ingredients, hydrophilicsurfactants, lipophilic surfactants and triglycerides. In anotherembodiment, the solid pharmaceutical composition includes a solidcarrier, the solid carrier being formed of different combinations ofpharmaceutical active ingredients, hydrophilic surfactants, lipophilicsurfactants and triglycerides. These and other embodiments, as well aspreferred aspects thereof; are described in more detail below.

It should be appreciated that any of the components of the compositionsof the present invention can be used as supplied commercially, or can bepreprocessed by agglomeration, air suspension chilling, air suspensiondrying, balling, coacervation, comminution, compression, pelletization,cryopelletization, extrusion, granulation, homogenization, inclusioncomplexation, lyophilization, melting, mixing, molding, pan coating,solvent dehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or other processes known in the art. Thevarious components can also be pre-coated or encapsulated. These variousprocesses and coatings are described in more detail below.

1. Pharmaceutical Active Ingredients

In the embodiments of the present invention, which include activeingredients, the active ingredients suitable for use in thepharmaceutical compositions and methods of the present invention are notparticularly limited, as the compositions are surprisingly capable ofeffectively delivering a wide variety of active ingredients. The activeingredients can by hydrophilic, lipophilic, amphiphilic or hydrophobic,and can be solubilized, dispersed, or partially solubilized anddispersed, in the encapsulation coat. Alternatively, the activeingredient can be provided separately from the solid pharmaceuticalcomposition, such as for co-administration. Such active ingredients canbe any compound or mixture of compounds having therapeutic or othervalue when administered to an animal, particularly to a mammal, such asdrugs, nutrients, cosmeceuticals, diagnostic agents, nutritional agents,and the like. It should be appreciated that the categorization of anactive ingredient as hydrophilic or hydrophobic may change, dependingupon the particular salts, isomers, analogs and derivatives used.

In one embodiment, the active ingredient agent is hydrophobic.Hydrophobic active ingredients are compounds with little or no watersolubility. Intrinsic water solubilities (i.e., water solubility of theunionized form) for hydrophobic active ingredients are less than about1% by weight, and typically less than about 0.1% or 0.01% by weight, Ina particular aspect of this embodiment, the active ingredient is ahydrophobic drug. In other particular aspects, the active ingredient isa nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.

Suitable hydrophobic active ingredients are not limited by therapeuticcategory, and can be, for example, analgesics, anti-inflammatory agents,antihelminthics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppresants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, Cox-2inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,anti-osteoporosis agents, anti-obesity agents, cognition enhancers,anti-urinary incontinence agents, nutritional oils, anti-benign prostatehypertrophy agents, essential fatty acids, non-essential fatty acids,and mixtures thereof.

Specific, non-limiting examples of suitable hydrophobic activeingredients are acetretin, albendazole, albuterol, aminoglutethimide,amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin,atovaquone, azithromycin, baclofen, beclomethasone, benezepril,benzonatate, betamethasone, bicalutanide, budesonide, bupropion,busulfan, butenafine, calcifediol, calcipotriene, calcitriol,camptothecin, candesartan, capsaicin, carbamezepine, carotenes,celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol,cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride,clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel,codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, danazol,dantrolene, dexchlorpheniramine, diclofenac, dicoumarol, digoxin,dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol,dirithromycin, donezepil, efavirenz, eprosartan, ergocalciferol,ergotamine, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fentanyl, fexofenadine, finasteride,fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan,furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide,glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen,irbesartan, irinotecan, isosorbide dinitrate, isotretinoin,itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine,lansoprazole, leflunomide, lisinopril, loperamide, loratadine,lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone,mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen,metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone,montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir,nifedipine, nisoldipine, nilutanide, nitrofurantoin, nizatidine,omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, pantoprazole,paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin,pravastatin, prednisolone, probucol, progesterone, pseudoephedrine,pyridostigmine, rabeprazole, raloxifene, repaglinide, rifabutine,rifapentine, rimexolone, ritanovir, rizatriptan, rofecoxib,rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate,simvastatin, sirolimus, spironolactone, sumatriptan, tacrine,tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan,teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagabine,ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremifene,tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone,valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D,vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, andzopiclone. Of course, salts, isomers and derivatives of the above-listedhydrophobic active ingredients may also be used, as well as mixturesthereof.

Among the above-listed hydrophobic active ingredients, preferred activeingredients include: acetretin, albendazole, albuterol,aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B,atorvastatin, atovaquone, azithromycin, baclofen, benzonatate,bicalutanide, busulfan, butenafine, calcifediol, calcipotrienc,calcitriol, camptothecin, capsaicin, carbamezepine, carotenes,celecoxib, cerivastatin, chlorpheniramine, cholecaliferol, cimetidine,cinnarizine, ciprofloxacin, cisapride, cetirizine, clarithromycin,clemastine, clomiphene, codeine, coenzyme Q10, cyclosporin, danazol,dantrolene, dexchlorpheniramine, diclofenac, digoxin,dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol,dirithromycin, donezepil, efavirenz, ergocalciferol, ergotamine,esomeprazole, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fentanyl, fexofenadine, finasteride,fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan,furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide,glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen,irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole,ketorolac, lamotrigine, lansoprazole, leflunomide, loperamide,loratadine, lovastatin, L-thryroxine, lutein, lycopene, mifepristone,mefloquine, megestrol acetate, methdone, methoxsalen, metronidazole,miconazole, midazolam, miglitol, mitoxantrone, medroxyprogesterone,montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir,nilutanide, nitrofurantoin, nizatidine, omeprazole, oestradiol,oxaprozin, paclitaxel, paracalcitol, pentazocine, pioglitazone,pizofetin, pravastatin, probucol, progesterone, pseudoephedrine,pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide,rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan,rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin,sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen,tamsulosin, targretin, tazarotene, teniposide, terbinafine,tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan,toremifene, tramadol, tretinoin, troglitazone, trovafloxacin,verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K,zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone,pharmaceutically acceptable salts, isomers and derivatives thereof, andmixtures thereof.

Particularly preferred hydrophobic active ingredients include:acetretin, albuterol, aminoglutethimide, amiodarone, amlodipine,amprenavir, atorvastatin, atovaquone, baclofen, benzonatate,bicalutanide, busulfan, calcifediol, calcipotriene, calcitriol,camptothecin, capsaicin, carbamezepine, carotenes, celecoxib,chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, cisapride,cetirizine, clemastine, coenzyme Q10, cyclosporin, danazol, dantrolene,dexchlorpheniramine, diclofenac, dehydroepiandrosterone,dihydroergotamine, dihydrotachysterol, efavirenz, ergocalciferol,ergotamine, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fexofenadine, finasteride, fluconazole,flurbiprofen, fosphenytoin, frovatriptan, furazolidone, glibenclamide,glipizide, glyburide, glimepiride, ibuprofen, irinotecan, isotretinoin,itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine,lansoprazole, leflunomide, loperamide, loratadine, lovastatin,L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone,megestrol acetate, methoxsalen, metronidazole, miconazole, miglitol,mitoxantrone, montelukast, nabumetone, naratriptan, nelfinavir,nilutanide, nitrofurantoin, nizatidine, omeprazole, oestradiol,oxaprozin, paclitaxel, paracalcitol, pioglitazone, pizofetin,pranlukast, probucol, progesterone, pseudoephedrine, rabeprazole,raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone,ritanovir, rizatriptan, rosiglitazone, saquinavir, sildenafil citrate,simvastatin, sirolimus, tacrolimus, tamoxifen, tamsulosin, targretin,tazarotene, teniposide, terbenafine, tetrahydrocannabinol, tiagabine,tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,troglitazone, trovafloxacin, ubidecarenone, vigabatrin, vitamin A,vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, ziprasidone,zolmitriptan, pharmaceutically acceptable salts, isomers and derivativesthereof, and mixtures thereof.

Most preferred hydrophobic active ingredients include: amlodipine,amprenavir, anagrelide, aprepitant, aripiprazole, atorvastatin,atovaquone, bosentan, budesonide, buproprion, carvedilol, celecoxib,cilosthzol, cisapride, clarithromycin, clozapine, clonazepam, coenzymeQ10, cyclosporin, dihydroergotamine, dronabinol, efavirenz, entacapone,eplerenone, eprosartan, estazolam, famotidine, felodipine, fenofibrate,fexofenadine, finasteride, gatifloxacin, haloperidol, ibuprofen,imipramine, isradipine, itraconazole, lamotragine, lansoprazole,lercanidipine, levofloxacin, loratadine, lovastatin, megestrol acetate,megestrol acetate, meloxicam, montelukast, nabumetone, nisoldipine,nizatidine, norfloxacin, olanzapine, omeprazole, oxandrolone, oxaprozin,oxybutynin, oxycarbazepine, paclitaxel, paracalcitol, pioglitazone,pranlukast, prednisone, progesterone, pseudoephedrine, quetiapine,rabeprazole, raloxifene, ramipril, rapamycin, risperidone, rofecoxib,repaglinide, rimexolone, ritanovir, ropinirole, rosiglitazone,rufinamide, saquinavir, sildenafil, sildenafil citrate, simvastatin,sirolimus, spironolactone, tacrine, tacrolimus, tamoxifen, tamsulosin,tegaserod, teniposide, testosterone undecanoate, terbenafine,tetrahydrocannabinol, thalidomide, tiagabine, ticlopidine, tizanidine,tolcapone, tolterodine, tramadol, troglitazone, valsartan, vitamin A,vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, ziprasidone,pharmaceutically acceptable salts, isomers and derivatives thereof, andmixtures thereof.

In another embodiment, the active ingredient is hydrophilic. Amphiphiliccompounds are also included within the class of hydrophilic activeingredients. Apparent water solubilities for hydrophilic activeingredients are greater than about 0.1% by weight and typically greaterthan about 1% by weight. In other particular aspects, the hydrophilicactive ingredient is a cosmeceutical, a diagnostic agent, or anutritional agent.

Suitable hydrophilic active ingredients are not limited by therapeuticcategory, and can be for example, analgesics, anti-inflammatory agents,antihelminthics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppresants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers,cardiac inotropic agent; corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, Cox-2inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,anti-osteoporosis agents, anti-obesity agents, cognition enhancers,anti-urinary incontinence agents, nutritional oils, anti-benign prostatehypertrophy agents, essential fatty acids, non-essential fatty acids,and mixtures thereof.

Likewise, the hydrophilic active ingredients can be a cytokine, apeptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, avaccine, a nucleoside, a nucleotide, a portion of genetic material, anucleic acid, or a mixture thereof.

Specific, non-limiting examples of suitable hydrophilic activeingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholinechloride; alatrofloxacin; alendronate; alglucerase; amantadinehydrochloride; ambenomium; amifostine; amiloride hydrochloride;aminocaproic acid; amphotericin B; antihemophilic factor (human);antihemophilic factor (porcine); antihemophilic factor (recombinant);aprotinin; asparaginase; atenolol; atracurium besylate; atropine;azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona;bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitoninsalmon; carboplatin; capecitabine; capreomycin sulfate; cefamandolenafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicidsodium; cefoperazone; cefotetan disodium; cefotaxime; cefoxitin sodium;ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirinsodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin;cladribine; clidinium bromide; clindamycin and clindamycin derivatives;ciprofloxacin; clodronate; colistimethate sodium; colistin sulfate;corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparinsodium; danaparoid; desferrioxamine; denileukin diflitox; desmopressin;diatrizoate meglumine and diatrizoate sodium; dicyclomine; didanosine;dirithromycin; dopamine hydrochloride; dornase alpha; doxacuriumchloride; doxorubicin, etidronate disodium; enalaprilat; enkephalin;enoxaparin; enoxaparin sodium; ephedrine; epinephrine; epoetin alpha;erythromycin; esmolol hydrochloride; factor IX; famciclovir;fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocytecolony stimulating factor; granulocyte-macrophage stimulating factor;recombinant human growth hormones; bovine growth hormone; gentamycin;glucagon; glycopyrolate; gonadotropin releasing hormone and syntheticanalogs thereof; GnRH; gonadorelin; grepafloxacin; haemophilus Bconjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis Bvirus vaccine inactivated; heparin sodium; indinavir sulfate; influenzavirus vaccine; interleukin-2; interleukin-3; insulin-human; insulinlispro; insulin procine; insulin NPH; insulin aspart; insulin glargine;insulin detemir; interferon alpha; interferon beta; ipratropium bromide;ifosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorincalcium; leuprolide acetate; levofloxacin; lincomycin and lincomycinderivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measlesvirus vaccine; meningococcal vaccine; menotropins; mepenzolate bromide;mesalamine; methenamine; methotrexate; methscopolamine; metforminhydrochloride; metoprolol; mezocillin sodium; mivacurium chloride; mumpsviral vaccine; nedocromil sodium; neostigmine bromide; neostigminemethyl sulfate; neurontin; norfloxacin; octreotide acetate; ofloxacin;olpadronate; oxytocin; pamidronate disodium; pancuronium bromide;paroxetine; perfloxacin; pentamidine isethionate; pentostatin;pentoxifylline; periciclovir, pentagastrin; phentolamine mesylate;phenylalanine; physostigmine salicylate; plague vaccine; piperacillinsodium; platelet derived growth factor; pneumococcal vaccine polyvalent;poliovirus vaccine (inactivated); poliovirus vaccine live (OPV);polymyxin B sulfate; pralidoxime chloride; pramlintide; pregabalin;propafenone; propantheline bromide; pyridostigmine bromide; rabiesvaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirusvaccine; salmeterol xinafoate; sincalide; small pox vaccine; solatol;somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase;streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutalinesulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue typeplasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexategluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumornecrosis factor; typhoid vaccine live; urea; urokinase; vancomycin;valacyclovir; valsartan; varicella virus vaccine live; vasopressin andvasopressin derivatives; vecuronium bromide; vinblastine; vincristine;vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine;zalcitabine; zanamivir; zolendronate; zidovudine; pharmaceuticallyacceptable salts, isomers and derivatives thereof; and mixtures thereof.

Among the above-listed hydrophilic active ingredients, preferred activeingredients include acarbose; acyclovir; atracurium besylate;alendronate; alglucerase; amantadine hydrochloride; amphotericin B;antihemophilic factor (human); antihemophilic factor (porcine);antihemophilic factor (recombinant); azithromycin; calcitonin human;calcitonin salmon; capecitabine; cefazolin sodium; cefonicid sodium;cefoperazone; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroximeaxetil; cephalexin; chorionic gonadotropin; cidofovir; cladribine;clindamycin and clindamycin derivatives; corticotropin; cosyntropin;cromolyn sodium; cytarabine; dalteparin sodium; danaparoid;desmopressin; didanosine; dirithromycin; etidronate disodium; enoxaparinsodium; epoetin alpha; factor IX; famciclovir; fludarabine; foscarnetsodium; ganciclovir; granulocyte colony stimulating factor;granulocyte-macrophage stimulating factor; recombinant human growthhormones; bovine growth hormone; gentamycin; glucagon; gonadotropinreleasing hormone and synthetic analogs thereof; GnRH; gonadorelin;haemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated;Hepatitis B virus vaccine inactivated; heparin sodium; indinavirsulfate; influenza virus vaccine; interleukin-2; interleukin-3;insulin-human; insulin lispro; procine; insulin NPH; aspart; insulinglargine; insulin determir; interferon alpha; interferon beta;ipratropium bromide; ifosfamide; lamivudine; leucovorin calcium;leuprolide acetate; lincomycin and lincomycin derivatives; metforminhydrochloride; nedocromil sodium; neostigmine bromide; neostigminemethyl sulfate; neurontin; octreotide acetate; olpadronate; pamidronatedisodium; pancuronium bromide; pentamidine isethionate; pentagastrin;physostigmine salicylate; poliovirus vaccine live (OPV); pyridostigminebromide; residronate; ribavarin; rimantadine hydrochloride; rotavirusvaccine; salmeterol xinafoate; somatostatin; spectinomycin; stavudine;streptokinase; ticarcillin; tiludronate; tissue type plasminogenactivator; TNFR:Fc; TNK-tPA; trimetrexate gluconate; trospectinomycin;tumor necrosis factor; typhoid vaccine live; urokinase; vancomycin;valacyclovir; vasopressin and vasopressin derivatives; vinblastine;vincristine; vinorelbine; warfarin sodium; zalcitabine; zanamivir;zidovudine; pharmaceutically acceptable salts, isomers and derivativesthereof; and mixtures thereof.

Most preferred hydrophilic active ingredients include acamprosate,acarbose; alendronate; amantadine hydrochloride; azithromycin;calcitonin human; calcitonin salmon; ceftriaxone; cefuroxime axetil;chorionic gonadotropin; cromolyn sodium; dalteparin sodium; danaparoid;desmopressin; didanosine; etidronate disodium; enoxaparin sodium;epoetin alpha; factor IX; famciclovir; foscarnet sodium; galantamine,ganciclovir; granulocyte colony stimulating factor;granulocyte-macrophage stimulating factor; recombinant human growthhormones; bovine growth hormone; glucagon; gonadotropin releasinghormone and synthetic analogs thereof, GnRH; gonadorelin; heparinsodium; indinavir sulfate; influenza virus vaccine; interleukin-2;interleukin-3; insulin-human; insulin lispro; insulin procine interferonalpha; interferon beta; leuprolide acetate; metformin hydrochloride;nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;neurontin; nitrofurantoin, octreotide acetate; olpadronate; pamidronatedisodium; residronate; rimantadine hydrochloride; salmeterol xinafoate;somatostatin; stavudine; ticarcillin; tiludronate; tissue typeplasminogen activator; TNFR:Fc; TNK-tPA; tumor necrosis factor; typhoidvaccine live; vancomycin; valacyclovir; vasopressin and vasopressinderivatives; zalcitabine; zanamivir; zidovudine; pharmaceuticallyacceptable salts, isomers and derivatives thereof; and mixtures thereof.

2. Surfactants

Various embodiments of the invention, as described in more detail below,include a hydrophilic surfactant. Hydrophilic surfactants can be used toprovide any of several advantageous characteristics to the compositions,including: increased solubility of the active ingredient in the solidcarrier, improved dissolution of the active ingredient; improvedsolubilization of the active ingredient upon dissolution; enhancedabsorption and/or bioavailability of the active ingredient, particularlya hydrophilic active ingredient; and improved stability, both physicaland chemical, of the active ingredient. The hydrophilic surfactant canbe a single hydrophilic surfactant or a mixture of hydrophilicsurfactants, and can be ionic or non-ionic.

Likewise, various embodiments of the invention include a lipophiliccomponent, which can be a lipophilic surfactant, including a mixture oflipophilic surfactants, a triglyceride, or a mixture thereof. Thelipophilic surfactant can provide any of the advantageouscharacteristics listed above for hydrophilic surfactants, as well asfurther enhancing the function of the surfactants. These variousembodiments are described in more detail below. For convenience, thesurfactants are described in this section, and the triglycerides in thesection that follows.

As is well known in the art, the terms “hydrophilic” and “lipophilic”are relative terms. To function as a surfactant, a compound mustnecessarily include polar or charged hydrophilic moieties as well asnon-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compoundmust be amphiphilic. An empirical parameter commonly used tocharacterize the relative hydrophilicity and lipophilicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (the “HLB”value). Surfactants with lower HLB values are more lipophilic, and havegreater solubility in oils, whereas surfactants with higher HLB valuesare more hydrophilic, and have greater solubility in aqueous solutions.

Using HLB values as a rough guide, hydrophilic surfactants are generallyconsidered to be those compounds having an HLB value greater than about10, as well as anionic, cationic, or zwitterionic compounds for whichthe HLB scale is not generally applicable. Similarly, lipophilicsurfactants are compounds having an HLB value less than about 10.

It should be appreciated that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many important surfactants,including several polyethoxylated surfactants, it has been reported thatHLB values can differ by as much as about 8 HLB units, depending uponthe empirical method chosen to determine the HLB value (Schott, J.Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certainpolypropylene oxide containing block copolymers (poloxamers, availablecommercially as PLURONIC® surfactants, BASF Corp), the HLB values maynot accurately reflect the true physical chemical nature of thecompounds. Finally, commercial surfactant products are generally notpure compounds, but are often complex mixtures of compounds, and the HLBvalue reported for a particular compound may more accurately becharacteristic of the commercial product of which the compound is amajor component. Different commercial products having the same primarysurfactant component can, and typically do, have different HLB values.In addition, a certain amount of lot-to-lot variability is expected evenfor a single commercial surfactant product. Keeping these inherentdifficulties in mind, and using HLB values as a guide, one skilled inthe art can readily identify surfactants having suitable hydrophilicityor lipophilicity for use in the present invention, as described herein.

Surfactants can be any surfactant suitable for use in pharmaceuticalcompositions. Suitable surfactants can be anionic, cationic,zwitterionic or non-ionic. Such surfactants can be grouped into thefollowing general chemical classes detailed in the Tables herein. TheHLB values given in the Tables below generally represent the HLB valueas reported by the manufacturer of the corresponding commercial product.In cases where more than one commercial product is listed, the HLB valuein the Tables is the value as reported for one of the commercialproducts, a rough average of the reported values, or a value that, inthe judgment of the present inventors, is more reliable.

It should be emphasized that the invention is not limited to thesurfactants in the Tables, which show representative, but not exclusive,lists of available surfactants. In addition, refined, distilled orfractionated surfactants, purified fractions thereof, or re-esterifiedfractions, are also within the scope of the invention, although notspecifically listed in the Tables.

2.1. Polyethoxylated Fatty Acids

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Examples of polyethoxylated fatty acid monoester surfactantscommercially available are shown in Table 1.

TABLE 1 PEG-Fatty Acid Monoester Surfactants COMPOUND COMMERCIAL PRODUCT(Supplier) HLB PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG4-100 monooleate Crodet O series (Croda) >8 PEG 4-100 monostearateCrodet S series (Croda), Myrj Series (Atlas/ICI) >6 PEG 400 distearateCithrol 4DS series (Croda) >10 PEG 100, 200, 300 monolaurate Cithrol MLseries (Croda) >10 PEG 100, 200, 300 monooleate Cithrol MO series(Croda) >10 PEG 400 dioleate Cithrol 4DO series (Croda) >10 PEG 400-1000monostearate Cithrol MS series (Croda) >10 PEG-1 stearate Nikkol MYS-1EX(Nikko), Coster K1 (Condea) 2 PEG-2 stearate Nikkol MYS-2 (Nikko) 4PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg ® 200 ML(PPG), Kessco ® PEG 200 ML (Stepan), 9.3 LIPOPEG 2L (Lipo Chem.) PEG-4oleate Mapeg ® 200 MO (PPG), Kessco ® PEG200 MO (Stepan), 8.3 PEG-4stearate Kessco ® PEG 200 MS (Stepan), Hodag 20 S (Calgene), 6.5 NikkolMYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleateNikkol TMGO-5 (Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA),Kessco ® PEG 300 MO 8.5 Stepan), Nikkol MYO-6 (Nikko), Emulgante A6(Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurateKessco ® PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7 (Condea) 13PEG-6 stearate Kessco ® PEG300 MS (Stepan) 9.7 PEG-8 laurate Mapeg ® 400ML (PPG), LIPOPEG 4DL (Lipo Chem.) 13 PEG-8 oleate Mapeg ® 400 MO (PPG),Emulgante A8 (Condea) 12 PEG-8 stearate Mapeg ® 400 MS (PPG), Myrj 45 12PEG-9 oleate Emulgante A9 (Condea) >10 PEG-9 stearate Cremophor S9(BASF) >10 PEG-10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) 13PEG-10 oleate Nikkol MYO-10 (Nikko) 11 PEG-10 stearate Nikkol MYS-10(Nikko), Coster K100 (Condea) 11 PEG-12 laurate Kessco ® PEG 600ML(Stepan) 15 PEG-12 oleate Kessco ® PEG 600MO (Stepan) 14 PEG-12ricinoleate (CAS # 9004-97-1) >10 PEG-12 stearate Mapeg ® 600 MS (PPG),Kessco ® PEG 600MS (Stepan) 14 PEG-15 stearate Nikkol TMGS-15 (Nikko),Koster K15 (Condea) 14 PEG-15 oleate Nikkol TMGO-15 (Nikko) 15 PEG-20laurate Kessco ® PEG 1000 ML (Stepan) 17 PEG-20 oleate Kessco ® PEG 1000MO (Stepan) 15 PEG-20 stearate Mapeg ® 1000 MS (PPG), Kessco ® PEG 1000MS Stepan), 16 Myrj 49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15 PEG-32laurate Kessco ® PEG 1540 ML (Stepan) 16 PEG-32 oleate Kessco ® PEG 1540MO (Stepan) 17 PEG-32 stearate Kessco ® PEG 1540 MS (Stepan) 17 PEG-30stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9 PEG-40oleate Crodet O40 (Croda) 17.4 PEG-40 stearate Myrj 52, Emerest ® 2715(Henkel), Nikkol MYS-40 (Nikko) >10 PEG-45 stearate Nikkol MYS-45(Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-55 stearate Nikkol MYS-55(Nikko) 18 PEG-100 oleate Crodet O-100 (Croda) 18.8 PEG-100 stearateMyrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200 MO (TaiwanSurf.) >10 PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (TaiwanSurf.) >10 PEG-600 oleate Albunol 600 MO (Taiwan Surf.) >10

2.2 PEG-Fatty Acid Diesters

Polyethylene glycol (PEG) fatty acid diesters are also suitable for useas surfactants in the compositions of the present invention.Representative PEG-fatty acid diesters are shown in Table 2.

TABLE 2 PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL PRODUCT(Supplier) HLB PEG-4 dilaurate Mapeg ® 200 DL (PPG), Kessco ® PEG 200 DL(Stepan), 7 LIPOPEG 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg ® 200 DO(PPG), 6 PEG-4 distearate Kessco ® 200 DS (Stepan) 5 PEG-6 dilaurateKessco ® PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco ® PEG 300 DO(Stepan) 7.2 PEG-6 distearate Kessco ® PEG 300 DS (Stepan) 6.5 PEG-8dilaurate Mapeg ® 400 DL (PPG), Kessco ® PEG 400 DL (Stepan), 11 LIPOPEG4 DL (Lipo Chem.) PEG-8 dioleate Mapeg ® 400 DO (PPG), Kessco ® PEG 400DO (Stepan), 8.8 LIPOPEG 4 O(Lipo Chem.) PEG-8 distearate Mapeg ® 400 DS(PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10 PEG-12dilaurate Kessco ® PEG 600 DL (Stepan) 11.7 PEG-12 distearate Kessco ®PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg ® 600 DO (PPG), Kessco ®600 DO(Stepan) 10 PEG-20 dilaurate Kessco ® PEG 1000 DL (Stepan) 15PEG-20 dioleate Kessco ® PEG 1000 DO (Stepan) 13 PEG-20 distearateKessco ® PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco ® PEG 1540 DL(Stepan) 16 PEG-32 dioleate Kessco ® PEG 1540 DO (Stepan) 15 PEG-32distearate Kessco ® PEG 1540 DS (Stepan) 15 PEG-400 dioleate Cithrol 4DOseries (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10

2.3 PEG-Fatty Acid Mono- and Di-Ester Mixtures

In general, mixtures of surfactants are also useful in the presentinvention, including mixtures of two or more commercial surfactantproducts. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters. Representative surfactant mixtures areshown in Table 3.

TABLE 3 PEG-Fatty Acid Mono- and Diester Mixtures COMPOUND COMMERCIALPRODUCT (Supplier) PEG 4-150 mono, Kessco ® PEG 200-6000 mono, dilaurate(Stepan) dilaurate PEG 4-150 mono, Kessco ® PEG 200-6000 mono, dioleate(Stepan) dioleate PEG 4-150 mono, Kessco ® 200-6000 mono, distearate(Stepan) distearate

2.4 Polyethylene Glycol Glycerol Fatty Acid Esters

Suitable PEG glycerol fatty acid esters arc shown in Table 4.

TABLE 4 PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT(Supplier) HLB PEG-20 glyceryl Tagat ® L (Goldschmidt) 16 laurate PEG-30glyceryl Tagat ® L2 (Goldschmidt) 16 laurate PEG-15 glyceryl Glycerox Lseries (Croda) 15 laurate PEG-40 glyceryl Glycerox L series (Croda) 15laurate PEG-20 glyceryl Capmul ® EMG (ABITEC), Aldo ® 13 stearate MS-20KFG (Lonza) PEG-20 glyceryl Tagat ® O (Goldschmidt) >10 oleate PEG-30glyceryl Tagat ® O2 (Goldschmidt) >10 oleate

2.5. Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of lipophilicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Representative surfactants of this class suitable foruse in the present invention are shown in Table 5.

TABLE 5 Transesterification Products of Oils and Alcohols COMPOUNDCOMMERCIAL PRODUCT (Supplier) HLB PEG-3 castor oil Nikkol CO-3 (Nikko) 3PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7 PEG-20 castoroil Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) 11 PEG-23castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (NihonEmulsion), Alkamuls ® EL 620 11 (Rhone-Poulenc), Incrocas 30 (Croda)PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35(Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65(Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), Alkamuls ® EL719 13 (Rhone-Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10 PEG-60 castor oilNikkol CO-60TX (Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castoroil Eumulgin ® PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated castor oilNikkol HCO-5 (Nikko) 6 PEG-7 hydrogenated castor oil Simusol ® 989(Seppic), Cremophor WO7 (BASF) 6 PEG-10 hydrogenated castor oil NikkolHCO-10 (Nikko) 6.5 PEG-20 hydrogenated castor oil Nikkol HCO-20 (Nikko)11 PEG-25 hydrogenated castor oil Simulsol ® 1292 (Seppic), Cerex ELS250 (Auschem 11 SpA) PEG-30 hydrogenated castor oil Nikkol HCO-30(Nikko) 11 PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF),Croduret (Croda), 13 Emulgin HRE 40 (Henkel) PEG-45 hydrogenated castoroil Cerex ELS 450 (Auschem Spa) 14 PEG-50 hydrogenated castor oil EmalexHC-50 (Nihon Emulsion) 14 PEG-60 hydrogenated castor oil Nikkol HCO-60(Nikko); Cremophor RH 60 (BASF) 15 PEG-80 hydrogenated castor oil NikkolHCO-80 (Nikko) 15 PEG-100 hydrogenated castor oil Nikkol HCO -100(Nikko) 17 PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4 PEG-6almond oil Labrafil ® M 1966 CS (Gattefosse) 4 PEG-6 apricot kernel oilLabrafil ® M 1944 CS (Gattefosse) 4 PEG-6 olive oil Labrafil ® M 1980 CS(Gattefosse) 4 PEG-6 peanut oil Labrafil ® M 1969 CS (Gattefosse) 4PEG-6 hydrogenated palm kernel Labrafil ® M 2130 BS (Gattefosse) 4 oilPEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse) 4 PEG-6 trioleinLabrafil ® M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil ® WL 2609 BS(Gattefosse) 6-7 PEG-20 corn glycerides Crovol M40 (Croda) 10 PEG-20almond glycerides Crovol A40 (Croda) 10 PEG-25 trioleate TAGAT ® TO(Goldschmidt) 11 PEG-40 palm kernel oil Crovol PK-70 >10 PEG-60 cornglycerides Crovol M70(Croda) 15 PEG-60 almond glycerides Crovol A70(Croda) 15 PEG-4 caprylic/capric triglyceride Labrafac ® Hydro(Gattefosse), 4-5 PEG-8 caprylic/capric glycerides Labrasol(Gattefosse), Labrafac CM 10 (Gattefosse) >10 PEG-6 caprylic/capricglycerides SOFTIGEN ® 767 (Hüls), Glycerox 767 (Croda) 19 Lauroylmacrogol-32 glyceride GELUCIRE 44/14 (Gattefosse) 14 Stearoyl macrogolglyceride GELUCIRE 50/13 (Gattefosse) 13 Mono, di, tri, tetra esters ofSorbitoGlyceride (Gattefosse) <10 vegetable oils and sorbitolPentaerythrityl tetraisostearate Crodamol PTIS (Croda) <10Pentaerythrityl distearate Albunol DS (Taiwan Surf.) <10 Pentaerythrityltetraoleate Liponate PO-4 (Lipo Chem.) <10 Pentaerythrityl tetrastearateLiponate PS-4 (Lipo Chem.) <10 Pentaerythrityl Liponate PE-810 (LipoChem.), Crodamol PTC <10 tetracaprylate/tetracaprate (Croda)Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko)

2.6. Polyglycerized Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for thepresent invention. Examples of suitable polyglyceryl esters are shown inTable 6.

TABLE 6 Polyglycerized Fatty Acids COMPOUND COMMERCIAL PRODUCT(Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 isostearateNikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol ® 3GO (ABITEC),Drewpol 3-1-O (Stepan) 6.5 Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O(Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), Nikkol Hexaglyn 1-O(Nikko) 9 Polyglyceryl-10 laurate Nikkol Decaglyn 1-L (Nikko) 15Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14 Polyglyceryl-10stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleateNikkol Hexaglyn PR-15 (Nikko) >8 Polyglyceryl-10 linoleate NikkolDecaglyn 1-LN (Nikko) 12 Polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-O(Nikko) <10 Polyglyceryl-3 dioleate Cremophor GO32 (BASF) <10Polyglyceryl-3 distearate Cremophor GS32 (BASF) <10 Polyglyceryl-4pentaoleate Nikkol Tetraglyn 5-O (Nikko) <10 Polyglyceryl-6 dioleateCaprol ® 6G20 (ABITEC); Hodag PGO-62 (Calgene), 8.5 PLUROL OLEIQUE CC497 (Gattefosse) Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7Polyglyceryl-10 trioleate Nikkol Decaglyn 3-O (Nikko) 7 Polyglyceryl-10pentaoleate Nikkol Decaglyn 5-O (Nikko) 3.5 Polyglyceryl-10 septaoleateNikkol Decaglyn 7-O (Nikko) 3 Polyglyceryl-10 tetraoleate Caprol ® 10G40(ABITEC); Hodag PGO-62 (CALGENE), 6.2 Drewpol 10-4-O (Stepan)Polyglyceryl-10 decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10Polyglyceryl-10l decaoleate Drewpol 10-10-O (Stepan), Caprol 10G10O(ABITEC), 3.5 Nikkol Decaglyn 10-O Polyglyceryl-10 mono, dioleateCaprol ® PGE 860 (ABITEC) 11 Polyglyceryl polyricinoleate Polymuls(Henkel)  3-20

2.7. Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in the present invention. Examples of surfactants of this class aregiven in Table 7.

TABLE 7 Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT(Supplier) HLB Propylene glycol Capryol 90 (Gattefosse), Nikkol <10monocaprylate Sefsol 218 (Nikko) Propylene glycol Lauroglycol 90(Gattefosse), <10 monolaurate Lauroglycol FCC (Gattefosse) Propyleneglycol Lutrol OP2000 (BASF) <10 oleate Propylene glycol Mirpyl <10myristate Propylene glycol ADM PGME-03 (ADM), 3-4 monostearate LIPO PGMS(Lipo Chem.), Aldo ® PGHMS (Lonza) Propylene glycol <10 hydroxy stearatePropylene glycol PROPYMULS (Henkel) <10 ricinoleate Propylene glycol <10isostearate Propylene glycol Myverol P-O6 (Eastman) <10 monooleatePropylene glycol Captex ® 200 (ABITEC), >6 dicaprylate/dicaprateMiglyol ® 840 (Hüls), Neobee ® M-20 (Stepan) Propylene glycol Captex ®800 (ABITEC) >6 dioctanoate Propylene glycol LABRAFAC PG (Gattefosse) >6caprylate/caprate Propylene glycol >6 dilaurate Propylene glycolKessco ® PGDS (Stepan) >6 distearate Propylene glycol Nikkol Sefsol 228(Nikko) >6 dicaprylate Propylene glycol Nikkol PDD (Nikko) >6 dicaprate

2.8. Mixtures of Propylene Glycol Esters-Glycerol Esters

In general, mixtures of surfactants are also suitable for use in thepresent invention. In particular, mixtures of propylene glycol fattyacid esters and glycerol fatty acid esters are suitable and arecommercially available. Examples of these surfactants are shown in Table8.

TABLE 8 Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIALPRODUCT (Supplier) HLB Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 StearicATMOS 150 3-4

2.9. Mono- and Diglycerides

A particularly important class of surfactants is the class of mono- anddiglycerides. These surfactants are generally lipophilic. Examples ofthese surfactants are given in Table 9.

TABLE 9 Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL PRODUCT(Supplier) HLB Monopalmitolein (C16:1) (Larodan) <10 Monoelaidin (C18:1)(Larodan) <10 Monocaproin (C6) (Larodan) <10 Monocaprylin (Larodan) <10Monocaprin (Larodan) <10 Monolaurin (Larodan) <10 Glyceryl monomyristateNikkol MGM (Nikko) 3-4 (C14) Glyceryl monooleate (C18:1) PECEOL(Gattefosse), Hodag GMO-D, Nikkol MGO 3-4 (Nikko) Glyceryl monooleateRYLO series (Danisco), DIMODAN series (Danisco), 3-4 EMULDAN (Danisco),ALDO ® MO FG (Lonza), Kessco GMO (Stepan), MONOMULS ® series (Henkel),TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80(Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman) GlycerolOLICINE (Gattefosse) 3-4 monooleate/linoleate Glycerol monolinoleateMaisine (Gattefosse), Myverol 18-92, Myverol 18-06 3-4 (Eastman)Glyceryl ricinoleate Softigen ® 701 (Hüls), HODAG GMR-D (Calgene), 6ALDO ® MR (Lonza) Glyceryl monolaurate ALDO ® MLD (Lonza), Hodag GML(Calgene) 6.8 Glycerol monopalmitate Emalex GMS-P (Nihon) 4 Glycerolmonostearate Capmul ® GMS (ABITEC), Myvaplex (Eastman), Imwitor ® 5-9191 (Hüls), CUTINA ® GMS, Aldo ® MS (Lonza), Nikkol MGS series (Nikko)Glyceryl mono- and di-oleate Capmul ® GMO-K (ABITEC) <10 Glycerylpalmitic/stearic CUTINA MD-A, ESTAGEL-G18 <10 Glyceryl acetate Lamegin ®EE (Grünau GmbH) <10 Glyceryl laurate Imwitor ® 312 (Hüls), Monomuls ®90-45 (Grünau GmbH), 4 Aldo ® MLD (Lonza) Glyceryl Imwitor ® 375 (Hüls)<10 citrate/lactate/oleate/ linoleate Glyceryl caprylate Imwitor ® 308(Hüls), Capmul ® MCMC8 (ABITEC) 5-6 Glyceryl caprylate/caprate Capmul ®MCM (ABITEC) 5-6 Caprylic acid Imwitor ® 988 (Hüls) 5-6mono/diglycerides Caprylic/capric glycerides Imwitor ® 742 (Hüls) <10Mono-and diacetylated Myvacet ® 9-45, Myvacet ® 9-40, Myvacet ® 9-083.8-4   monoglycerides (Eastman), Lamegin ® (Grünau) Glycerylmonostearate Aldo ® MS, Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), 4.4Imwitor ® 191 (Hüls), Myvaplex (Eastman) Lactic acid esters of mono-LAMEGIN GLP (Henkel) <10 and di-glycerides Dicaproin (C6) (Larodan) <10Dicaprin (C10) (Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin(C14) (Larodan) <10 Dipalmitin (C16) (Larodan) <10 Distearin (Larodan)<10 Glyceryl dilaurate (C12) Capmul ® GDL (ABITEC) 3-4 Glyceryl dioleateCapmul ® GDO (ABITEC) 3-4 Glycerol esters of fatty acids GELUCIRE 39/01(Gattefosse), GELUCIRE 43/01 1 (Gattefosse) GELUCIRE 37/06 (Gattefosse)6 Dipalmitolein (C16:1) (Larodan) <10 1,2 and 1,3-diolein (C18:1)(Larodan) <10 Dielaidin (C18:1) (Larodan) <10 Dilinolein (C18:2)(Larodan) <10

2.10. Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inthe present invention. These surfactants can be hydrophilic orlipophilic. Examples of surfactants of this class are shown in Table 10.

TABLE 10 Sterol and Sterol Derivative Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Cholesterol, sitosterol, <10 lanosterol PEG-24cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol NikkolDHC (Nikko) >10 Phytosterol GENEROL series (Henkel) <10 PEG-25 phytosterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-5 (Nikko)<10 PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10 PEG-20 soya sterolNikkol BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10

2.11. Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in the present invention. In general,these surfactants are hydrophilic, although several lipophilicsurfactants of this class can be used. Examples of these surfactants areshown in Table 11.

TABLE 11 PEG-Sorbitan Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT(Supplier) HLB PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 (Croda),DACOL MLS 20 17 (Condea) PEG-4 sorbitan monolaurate Tween-21(Atlas/ICI), Crillet 11 (Croda) 13 PEG-80 sorbitan monolaurate HodagPSML-80 (Calgene); T-Maz 28 >10 PEG-6 sorbitan monolaurate Nikkol GL-1(Nikko) 16 PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), Crillet 2(Croda) 16 PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3(Croda) 15 PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31(Croda) 9.6 PEG-8 sorbitan monostearate DACOL MSS (Condea) >10 PEG-6sorbitan monostearate Nikkol TS106 (Nikko) 11 PEG-20 sorbitantristearate Tween-65 (Atlas/ICI), Crillet 35 (Croda) 11 PEG-6 sorbitantetrastearate Nikkol GS-6 (Nikko) 3 PEG-60 sorbitan tetrastearate NikkolGS-460 (Nikko) 13 PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI),Crillet 41 (Croda) 10 PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), Crillet 4 (Croda) 15PEG-40 sorbitan oleate Emalex ET 8040 (Nihon Emulsion) 18 PEG-20sorbitan trioleate Tween-85 (Atlas/ICI), Crillet 45 (Croda) 11 PEG-6sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleateNikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440(Nikko) 13 PEG-20 sorbitan Tween-120 (Atlas/ICI), Crillet 6 (Croda) >10monoisostearate PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6sorbitol hexastearate Nikkol GS-6 (Nikko) 3

2.12. Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in the present invention. Examples of thesesurfactants are shown in Table 12.

TABLE 12 Polyethylene Glycol Alkyl Ethers COMMERCIAL COMPOUND PRODUCT(Supplier) HLB PEG-2 oleyl ether, oleth-2 Brij 92/93 (Atlas/ICI) 4.9PEG-3 oleyl ether, oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl ether, oleth-10 Volpo 10(Croda), 12 Brij 96/97 (Atlas/ICI) PEG-20 oleyl ether, oleth-20 Volpo 20(Croda), 15 Brij 98/99 (Atlas/ICI) PEG-4 lauryl ether, laureth-4 Brij 30(Atlas/ICI) 9.7 PEG-9 lauryl ether >10 PEG-23 lauryl ether, Brij 35(Atlas/ICI) 17 laureth-23 PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10cetyl ether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2stearyl ether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12PEG-20 stearyl ether Brij 78 (ICI) 15 PEG-100 stearyl ether Brij 700(ICI) >10

2.13. Sugar Esters

Esters of sugars are suitable surfactants for use in the presentinvention. Examples of such surfactants are shown in Table 13.

TABLE 13 Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier)HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3 Crodesta F-10(Croda) Sucrose SUCRO ESTER 11 (Gattefosse), 12 distearate/monostearateCrodesta F-110 (Croda) Sucrose dipalmitate 7.4 Sucrose monostearateCrodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15(Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 1695 15(Mitsubishi-Kasei)

2.14. Polyethylene Glycol Alkyl Phenols

Several hydrophilic PEG-alkyl phenol surfactants are available, and aresuitable for use in the present invention. Examples of these surfactantsare shown in Table 14.

TABLE 14 Polyethylene Glycol Alkyl Phenol Surfactants COMMERCIALCOMPOUND PRODUCT (Supplier) HLB PEG-10-100 nonyl phenol Triton X series(Rohm & Haas), >10 Igepal CA series (GAF, USA), Antarox CA series (GAF,UK) PEG-15-100 octyl Triton N-series (Rohm & Haas), >10 phenol etherIgepal CO series (GAF, USA), Antarox CO series (GAF, UK)

2.15. Polyoxyethylene-Polyoxypropylene Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and lipophilic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in the presentinvention. These surfactants are available under various trade names,including Synperonic PE series (ICI), Pluoronic® series (BASF), Emkalyx,Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The genericterm for these polymers is “poloxamer” (CAS 9003-11-6). These polymershave the formula:

HO(C₂H₄O)_(n)(C₃H₆O)_(b)(C₂H₄O)_(a)H

where “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively.

Examples of suitable surfactants of this class are shown in Table 15.Since the compounds are widely available, commercial sources are notlisted in the Table. The compounds are listed by generic name, with thecorresponding “a” and “b” values.

TABLE 15 POE-POP Block Copolymers COMPOUND a, b values inHO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H HLB Poloxamer 105 a = 11 b = 16 8Poloxamer 108 a = 46 b = 16 >10 Poloxamer 122 a = 5 b = 21 3 Poloxamer123 a = 7 b = 21 7 Poloxamer 124 a = 11 b = 21 >7 Poloxamer 181 a = 3 b= 30 Poloxamer 182 a = 8 b = 30 2 Poloxamer 183 a = 10 b = 30 Poloxamer184 a = 13 b = 30 Poloxamer 185 a = 19 b = 30 Poloxamer 188 a = 75 b =30 29 Poloxamer 212 a = 8 b = 35 Poloxamer 215 a = 24 b = 35 Poloxamer217 a = 52 b = 35 Poloxamer 231 a = 16 b = 39 Poloxamer 234 a = 22 b =39 Poloxamer 235 a = 27 b = 39 Poloxamer 237 a = 62 b = 39 24 Poloxamer238 a = 97 b = 39 Poloxamer 282 a = 10 b = 47 Poloxamer 284 a = 21 b =47 Poloxamer 288 a = 122 b = 47 >10 Poloxamer 331 a = 7 b = 54 0.5Poloxamer 333 a = 20 b = 54 Poloxamer 334 a = 31 b = 54 Poloxamer 335 a= 38 b = 54 Poloxamer 338 a = 128 b = 54 Poloxamer 401 a = 6 b = 67Poloxamer 402 a = 13 b = 67 Poloxamer 403 a = 21 b = 67 Poloxamer 407 a= 98 b = 67

2.16. Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use in thepresent invention. Examples of these surfactants are shown in Table 16.

TABLE 16 Sorbitan Fatty Acid Ester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1(Croda), 8.6 Arlacel 20 (ICI) Sorbitan monopalmitate Span-40(Atlas/ICI), Crill 2 (Croda), 6.7 Nikkol SP-10 (Nikko) Sorbitanmonooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3 Crill 50 (Croda)Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), 4.7 NikkolSS-10 (Nikko) Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda),4.3 Nikkol SO-30 (Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Crill 43(Croda), 3.7 Nikkol SO-15 (Nikko) Sorbitan tristearate Span-65(Atlas/ICI) Crill 35 (Croda), 2.1 Nikkol SS-30 (Nikko) Sorbitanmonoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7 Sorbitansesquistearate Nikkol SS-15 (Nikko) 4.2

2.17. Lower Alcohol Fatty Acid Esters

Esters of lower alcohols (C₄ to C₄) and fatty acids (C₈ to C₁₈) aresuitable surfactants for use in the present invention. Examples of thesesurfactants are shown in Table 17.

TABLE 17 Lower Alcohol Fatty Acid Ester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Ethyl oleate Crodamol EO (Croda), Nikkol EOO(Nikko) <10 Isopropyl myristate Crodamol IPM (Croda) <10 Isopropylpalmitate Crodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko)<10 Isopropyl linoleate Nikkol VF-IP (Nikko) <10

2.18. Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in the presentinvention. Preferred anionic surfactants include fatty acid salts andbile salts. Preferred cationic surfactants include carnitines.Specifically, preferred ionic surfactants include sodium oleate, sodiumlauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine;palmitoyl carnitine; and myristoyl carnitine. Examples of suchsurfactants are shown in Table 18. For simplicity, typical counterionsare shown in the entries in the Table. It will be appreciated by oneskilled in the art, however, that any bioacceptable counterion may beused. For example, although the fatty acids are shown as sodium salts,other cation counterions can also be used, such as alkali metal cationsor ammonium. Unlike typical non-ionic surfactants, these ionicsurfactants are generally available as pure compounds, rather thancommercial (proprietary) mixtures. Because these compounds are readilyavailable from a variety of commercial suppliers, such as Aldrich,Sigma, and the like, commercial sources are not generally listed in theTable.

TABLE 18 Ionic Surfactants COMPOUND HLB FATTY ACID SALTS >10 Sodiumcaproate Sodium caprylate Sodium caprate Sodium laurate Sodium myristateSodium myristolate Sodium palmitate Sodium palmitoleate Sodium oleate 18Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearateSodium lauryl sulfate (dodecyl) 40 Sodium tetradecyl sulfate Sodiumlauryl sarcosinate Sodium dioctyl sulfosuccinate [sodium docusate(Cytec)] BILE SALTS >10 Sodium cholate Sodium taurocholate Sodiumglycocholate Sodium deoxycholate Sodium taurodeoxycholate Sodiumglycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholateSodium taurochenodeoxycholate Sodium glyco chenodeoxycholate Sodiumcholylsarcosinate Sodium N-methyl taurocholate PHOSPHOLIPIDS Egg/Soylecithin [Epikuron ® (Lucas Meyer), Ovothin ® (Lucas Meyer)] CardiolipinSphingomyelin Phosphatidylcholine Phosphatidyl ethanolamine Phosphatidicacid Phosphatidyl glycerol Phosphatidyl serine PHOSPHORIC ACID ESTERSDiethanolammonium polyoxyethylene-10 oleyl ether phosphateEsterification products of fatty alcohols or fatty alcohol ethoxylateswith phosphoric acid or anhydride CARBOXYLATES Ether carboxylates (byoxidation of terminal OH group of fatty alcohol ethoxylates)Succinylated monoglycerides [LAMEGIN ZE (Henkel)] Sodium stearylfumarate Stearoyl propylene glycol hydrogen succinate Mono/diacetylatedtartaric acid esters of mono- and diglycerides Citric acid esters ofmono-, diglycerides Glyceryl-lacto esters of fatty acids (CFR ref.172.852) Acyl lactylates: lactylic esters of fatty acids calcium/sodiumstearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate saltsPropylene glycol alginate SULFATES AND SULFONATES Ethoxylated alkylsulfates Alkyl benzene sulfones α-olefin sulfonates Acyl isethionatesAcyl taurates Alkyl glyceryl ether sulfonates Octyl sulfosuccinatedisodium Disodium undecylenamideo-MEA-sulfosuccinate CATIONICSURFACTANTS >10 Hexadecyl triammonium bromide Dodecyl ammonium chlorideAlkyl benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethylbenzylammonium salts Alkylpyridinium salts Betaines (trialkylglycine):Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines:Polyoxyethylene-15 coconut amine

2.19 Unionized Ionizable Surfactants

Ionizable surfactants, when present in their unionized (neutral,non-salt) form, are lipophilic surfactants suitable for use in thecompositions of the present invention. Particular examples of suchsurfactants include free fatty acids, particularly C₆-₂₂ fatty acids,and bile acids. More specifically, suitable unionized ionizablesurfactants include the free fatty acid and bile acid forms of any ofthe fatty acid salts and bile salts shown in Table 18.

2.20 Derivatives of Fat-Soluble Vitamins

Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc.,are also useful surfactants for the compositions of the presentinvention. An example of such a derivative is tocopheryl PEG-1000succinate (TPGS, available from Eastman).

2.21 Preferred Surfactants

Among the above-listed surfactants, several combinations are preferred.In general, surfactants or mixtures of surfactants that solidify atambient room temperature are most preferred. Also preferred aresurfactants or mixtures of surfactants that solidify at ambient roomtemperature in combination with particular lipophilic components, suchas triglycerides, or with addition of appropriate additives, such asviscosity modifiers, binders, thickeners, and the like.

Preferred non-ionic hydrophilic surfactants include alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethyleneglycol fatty acids esters; polyethylene glycol glycerol fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols with fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters; sugar ethers;sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives;and mixtures thereof.

More preferably, the non-ionic hydrophilic surfactant is selected fromthe group consisting of polyoxyethylene alkylethers; polyethylene glycolfatty acid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fattyacid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. The glyceride can be amonoglyceride, diglyceride, triglyceride, or a mixture.

Also preferred are non-ionic hydrophilic surfactants that are reactionmixtures of polyols and fatty acids, glycerides, vegetable oils,hydrogenated vegetable oils, or sterols. These reaction mixtures arelargely composed of the transesterification products of the reaction,along with complex mixtures of other reaction products. The polyol ispreferably glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

The hydrophilic surfactant can also be, or can include as a component,an ionic surfactant. Preferred ionic surfactants include alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fusidicacid and derivatives thereof; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acidsoligopeptides, and polypeptides; acyl lactylates; mono-and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylatedmonoglycerides; citric acid esters of mono- and di-glycerides; alginatesalts; propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; carnitines; andmixtures thereof.

More preferable ionic surfactants include bile acids and salts,analogues, and derivatives thereof; lecithins, lysolecithin,phospholipids, lysophospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates;mono- and di-acetylated tartaril acid esters of mono- and di-glycerides;succinylated monoglycerides; citric acid esters of mono- anddi-glycerides; carnitines; and mixtures thereof.

More specifically, preferred ionic surfactants are lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, phosphatidic acid, phosphatidylserine,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidyiglycerol, lysophosphatidic acid, lysophosphatidylserine,PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylicesters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate,succinylated monoglycerides, mono- and di-acetylated tartaric acidesters of mono- and di-glycerides, citric acid esters of mono- anddi-glycerides, cholate, taurocholate, glycocholate, deoxycholate,taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyltaurocholate, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoylcarnitines, myristoyl carnitines, and salts and mixtures thereof.

Particularly preferred ionic surfactants are lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic estersof fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylatedmonoglycerides, mono- and di-acetylated tartaric acid esters of mono-and di-glycerides, citric acid esters of mono- and di-glyceridescholate, taurocholate glycocholate, deoxycholate, taurodeoxycholate,glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate,laurate, oleate, lauryl sulfate, docusate, and salts and mixturesthereof, with the most preferred ionic surfactants being lecithin,lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyllactylate, succinylated monoglycerides, mono- and di-acetylated tartaricacid esters of mono- and di-glycerides, citric acid esters of mono- anddi-glycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate,docusate, and salts and mixtures thereof.

Preferred lipophilic surfactants are alcohols; polyoxyethylenealkylethers; fatty acids; glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lower alcohol fatty acid esters;polyethylene glycol fatty acid esters; polyethylene glycol glycerolfatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of mono- anddi-glycerides; propylene glycol diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylenehydrogenated vegetable oils.

As with the hydrophilic surfactants, lipophilic surfactants can bereaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols.

Preferably, the lipophilic surfactant is selected from the groupconsisting of fatty acids; lower alcohol fatty acid esters; polyethyleneglycol glycerol fatty acid esters; polypropylene glycol fatty acidesters; polyoxyethylene glycerides; glycerol fatty acid esters;acetylated glycerol fatty acid esters; lactic acid derivatives of mono-and di-glycerides; sorbitan fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; and reaction mixtures of polyols and fatty acids, glycerides,vegetable oils, hydrogenated vegetable oils, and sterols.

More preferred are lower alcohol fatty acids esters; polypropyleneglycol fatty acid esters; propylene glycol fatty acid esters; glycerolfatty acid esters; acetylated glycerol fatty acid esters; lactic acidderivatives of mono- and di-glycerides; sorbitan fatty acid esters;polyoxyethylene vegetable oils; and mixtures thereof, with glycerolfatty acid esters and acetylated glycerol fatty acid esters being mostpreferred. Among the glycerol fatty acid esters, the esters arepreferably mono- or diglycerides, or mixtures of mono- and diglycerides,where the fatty acid moiety is a C₆ to C₂₂ fatty acid.

Also preferred are lipophilic surfactants that are the reaction mixtureof polyols and fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols. Preferred polyols are polyethylene glycol,sorbitol, propylene glycol, and pentaerythritol.

3. Triglycerides

For compositions of the present invention that include a lipophilicadditive, the lipophilic component can be a lipophilic surfactant or atriglyceride. Preferred triglycerides are those which solidify atambient room temperature, with or without addition of appropriateadditives, or those which in combination with particular surfactantsand/or active ingredients solidify at room temperature. Examples oftriglycerides suitable for use in the present invention are shown inTable 19. In general, these triglycerides are readily available fromcommercial sources. For several triglycerides, representative commercialproducts and/or commercial suppliers are listed.

TABLE 19 Triglycerides TRIGLYCERIDE COMMERCIAL SOURCE Aceituno oilAlmond oil Super Refined Almond Oil (Croda) Arachis oil Babassu oilBlackcurrant seed oil Borage oil Buffalo ground oil Candlenut oil Canolaoil Lipex 108 (Abitec) Caster oil Chinese vegetable tallow oil Cocoabutter Coconut oil Coffee seed oil Pureco 76 (Abitec) Corn oil SuperRefined Corn Oil (Croda) Cottonseed oil Super Refined Cottonseed Oil(Croda) Crambe oil Cuphea species oil Evening primrose oil Grapeseed oilGroundnut oil Hemp seed oil Illipe butter Kapok seed oil Linseed oilMenhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustardseed oil Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oilPalm kernel oil Peanut oil Super Refined Peanut Oil (Croda) Poppy seedoil Rapeseed oil Rice bran oil Safflower oil Super Refined Safflower Oil(Croda) Sal fat Sesame oil Super Refined Sesame Oil (Croda) Shark liveroil Super Refined Shark Liver Oil (Croda) Shea nut oil Soybean oil SuperRefined Soybean Oil (Croda) Stillingia oil Sunflower oil Tall oil Teasead oil Tobacco seed oil Tung oil (China wood oil) Ucuhuba Vernonia oilWheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated casteroil Castorwax Hydrogenated coconut oil Pureco 100 (Abitec) Hydrogenatedcottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST(Abitec); Softisan154 (Hüls) Hydrogenated soybean oil Sterotex HM NF(Abitec); Dritex S (Abitec) Hydrogenated vegetable oil Sterotex NF(Abitec): Hydrokote M (Abitec) Hydrogenated cottonseed/castor oilSterotex K (Abitec) Partially hydrogenated soybean oil Hydrokote AP5(Abitec) Partially soy and cottonseed oil Apex B (Abitec) Glyceryltributyrate (Sigma) Glyceryl tricaproate (Sigma) Glyceryl tricaprylate(Sigma) Glyceryl tricaprate Captex 1000 (Abitec) Glyceryl trundecanoateCaptex 8227 (Abitec) Glyceryl trilaurate (Sigma) Glyceryl trimyristateDynasan 114 (Hüls) Glyceryl tripalmitate Dynasan 116 (Hüls) Glyceryltristearate Dynasan 118 (Hüls) Glyceryl triarcidate (Sigma) Glyceryltrimyristoleate (Sigma) Glyceryl tripalmitoleate (Sigma) Glyceryltrioleate (Sigma) Glyceryl trilinoleate (Sigma) Glyceryl trilinolenate(Sigma) Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355(Abitec); Miglyol 810 (Hüls); Miglyol 812 (Hüls) Glyceryltricaprylate/caprate/laurate Captex 350 (Abitec) Glyceryltricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hüls)Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hüls); (Larodan)Glyceryl tricaprylate/laurate/stearate (Larodan) Glyceryl1,2-caprylate-3-linoleate (Larodan) Glyceryl 1,2-caprate-3-stearate(Larodan) Glyceryl 1,2-laurate-3-myristate (Larodan) Glyceryl1,2-myristate-3-laurate (Larodan) Glyceryl 1,3-palmitate-2-butyrate(Larodan) Glyceryl 1,3-stearate-2-caprate (Larodan) Glyceryl1,2-linoleate-3-caprylate (Larodan)

Fractionated triglycerides, modified triglycerides, synthetictriglycerides, and mixtures of triglycerides are also within the scopeof the invention.

Preferred triglycerides include vegetable oils, fish oils, animal fats,hydrogenated vegetable oils, partially hydrogenated vegetable oils,medium and long-chain triglycerides, and structured triglycerides. Itshould be appreciated that several commercial surfactant compositionscontain small to moderate amounts of triglycerides, typically as aresult of incomplete reaction of a triglyceride starting material in,for example, a transesterification reaction. Such commercial surfactantcompositions, while nominally referred to as “surfactants,” may besuitable to provide all or part of the triglyceride component for thecompositions of the present invention. Examples of commercial surfactantcompositions containing triglycerides include some members of thesurfactant families Gelucires (Gattefosse), Maisines (Gattefosse), andImwitors (Hüls). Specific examples of these compositions are: Gelucire44/14 (saturated polyglycolized glycerides); Gelucire 50/13 (saturatedpolyglycolized glycerides); Gelucire 53/10 (saturated polyglycolizedglycerides); Gelucire 33/01 (semi-synthetic triglycerides of C₈-C₁₈saturated fatty acids); Gelucire 39/01 (semi-synthetic glycerides);other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09,50/02, 62/05, etc.; Maisine 35-I (linoleic glycerides); and Imwitor 742(caprylic/capric glycerides).

Still other commercial surfactant compositions having significanttriglyceride content are known to those skilled in the art. It should beappreciated that such compositions, which contain triglycerides as wellas surfactants, may be suitable to provide all or part of thetriglyceride component of the compositions of the present invention, aswell as all or part of the surfactant component.

4. Substrates

The substrate of the compositions of the present invention can be apowder or a multiparticulate, such as a granule, a pellet, a bead, aspherule, a beadlet, a microcapsule, a millisphere, a nanocapsule, ananosphere, a microsphere, a platelet, a minitablet, a tablet or acapsule. A powder constitutes a finely divided (milled, micronized,nanosized, precipitated) form of an active ingredient or additivemolecular aggregates or a compound aggregate of multiple components or aphysical mixture of aggregates of an active ingredient and/or additives.Such substrates can be formed of various materials known in the art,such as, for example: sugars, such as lactose, sucrose or dextrose;polysaccharides, such as maltodextrin or dextrates; starches;cellulosics, such as microcrystalline cellulose or microcrystallinecellulose/sodium carboxymethyl cellulose; inorganics, such as dicalciumphosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; andpolyols, such as mannitol, xylitol, sorbitol or cyclodextrin.

The substrate can also be formed of any of the active ingredients,surfactants, triglycerides, solubilizers or additives described herein.In one particular embodiment, the substrate is a solid form of anadditive, an active ingredient, a surfactant, or a triglyceride; acomplex of an additive, surfactant or triglyceride and an activeingredient; a coprecipitate of an additive, surfactant or triglycerideand an active ingredient, or a mixture thereof.

It should be emphasized that the substrate need not be a solid material,although often it will be a solid. For example, the encapsulation coaton the substrate may act as a solid “shell” surrounding andencapsulating a liquid or semi-liquid substrate material. Suchsubstrates are also within the scope of the present invention, as it isultimately the carrier, of which the substrate is a part, which must bea solid.

5. Additives

The solid pharmaceutical compositions of the present invention canoptionally include one or more additives, sometimes referred to asexcipients. The additives can be contained in an encapsulation coat incompositions, which include an encapsulation coat, or can be part of thesolid carrier, such as coated to an encapsulation coat, or containedwithin the components forming the solid carrier. Alternatively, theadditives can be contained in the pharmaceutical composition but notpart of the solid carrier itself. Specific, non-limiting examples ofadditives are described below.

Suitable additives are those commonly utilized to facilitate theprocesses involving the preparation of the solid carrier, theencapsulation coating, or the pharmaceutical dosage form. Theseprocesses include agglomeration, air suspension chilling, air suspensiondrying, balling, coacervation, comminution, compression, pelletization,cryopelletization, extrusion, granulation, homogenization, inclusioncomplexation, lyophilization, nanoencapsulation, melting, mixing,molding, pan coating, solvent dehydration, sonication, spheronization,spray chilling, spray congealing, spray drying, or other processes knownin the art. The additive can also be pre-coated or encapsulated.Appropriate coatings are well known in the art, and are furtherdescribed in the sections below. Based on the functionality of theadditives, examples of the additives are as follows:

5.1 Solubilizers

The pharmaceutical compositions of the present invention can optionallyinclude one or more solubilizers, i.e., additives to increase thesolubility of the pharmaceutical active ingredient or other compositioncomponents in the solid carrier. Suitable solubilizers for use in thecompositions of the present invention include:

alcohols and polyols, such as ethanol, isopropanol, butanol, benzylalcohol, ethylene glycol, propylene glycol, butanediols and isomersthereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol,dimethyl isosorbide, polyethylene glycol, polypropylene glycol,polyvinylalcohol, hydroxypropylmethyl cellulose and other cellulosederivatives, cyclodextrins and cyclodextrin derivatives;

ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol, available commercially from BASF under the trade nameTetraglycol) or methoxy PEG (Union Carbide);

amides, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;

esters, such as ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, ε-caprolactone and isomersthereof, δ-valerolactone and isomers thereof, β-butyrolactone andisomers thereof; and

and other solubilizers known in the art, such as dimethyl acetamide,dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones(Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether(available from Gattefosse under the trade name Transcutol), and water.

Mixtures of solubilizers are also within the scope of the invention.Except as indicated, these compounds are readily available from standardcommercial sources.

Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate,ethyl caprylate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol200-600, glycofurol, transcutol, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol,glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propyleneglycol.

The amount of solubilizer that can be included in compositions of thepresent invention is not particularly limited. Of course, when suchcompositions are ultimately administered to a patient, the amount of agiven solubilizer is limited to a bioacceptable amount, which is readilydetermined by one of skill in the art. In some circumstances, it may beadvantageous to include amounts of solubilizers far in excess ofbioacceptable amounts, for example, to maximize the concentration ofactive ingredient, with excess solubilizer removed prior to providingthe composition to a patient using conventional techniques, such asdistillation or evaporation.

5.2. Enzyme Inhibitors

When the active ingredient is subject to enzymatic degradation, thecompositions can include an enzyme inhibiting agent. Enzyme inhibitingagents are shown for example, in Bernskop-Schnurch, A., “The use ofinhibitory agents to overcome enzymatic barrier to perorallyadministered therapeutic peptides and proteins,” J. Controlled Release52, 1-16 (1998), the disclosure of which is incorporated herein byreference.

Generally, inhibitory agents can be divided into the following classes:

Inhibitors that are not based on amino acids, such asP-aminobenzamidine, FK-448, camostat mesylate, sodium glycocholate;

Amino acids and modified amino acids, such as aminoboronic acidderivatives and n-acetylcysteine;

Peptides and modified peptides, such as bacitracin, phosphinic aciddipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin,elastatin, bestatin, phosphoramindon, puromycin, cytochalasinpotatocarboxy peptidase inhibitor, and amastatin;

Polypeptide protease inhibitors, such as aprotinin (bovine pancreatictrypsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor,chicken egg white trypsin inhibitor, chicken ovoinhibitor, and humanpancreatic trypsin inhibitor. Complexing agents, such as EDTA, EGTA,1,10-phenanthroline and hydroxychinoline; and

Mucoadhesive polymers and polymer-inhibitor conjugates, such aspolyacrylate derivatives, chitosan, celluosics, chitosan-EDTA,chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethylcellulose-pepstatin, polyacrylic acid-Bowman-Birk inhibitor.

The choice and levels of the enzyme inhibitor are based on toxicity,specificity of the proteases and the potency of the inhibition. Theinhibitor can be suspended or solubilized in the compositionpreconcentrate, or added to the aqueous diluent or as a beverage.

Without wishing to be bound by theory, it is believed that an inhibitorcan function solely or in combination as a competitive inhibitor, bybinding at the substrate binding site of the enzyme, thereby preventingthe access to the substrate; examples of inhibitors believed to operateby this mechanism are antipain, elastatinal and the Bowman Birkinhibitor; a non-competitive inhibitor which can be simultaneously boundto the enzyme site along with the substrate, as their binding sites arcnot identical; and/or a complexing agent due to loss in enzymaticactivity caused by deprivation of essential metal ions out of the enzymestructure.

5.3 Other Additives

Other additives conventionally used in pharmaceutical compositions canbe included, and these additives are well known in the art. Suchadditives include:

anti-adherents (anti-sticking agents, glidants, flow promoters,lubricants) such as talc, magnesium stearate, fumed silica (Carbosil,Aerosil), micronized silica (Syloid No. FP 244, Grace U.S.A.),polyethylene glycols, surfactants, waxes, stearic acid, stearic acidsalts, stearic acid derivatives, starch, hydrogenated vegetable oils,sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium laurylsulfate;

anticoagulants, such as acetylated monoglycerides;

antifoaming agents, such as long-chain alcohols and siliconederivatives;

antioxidants, such as BHT, BHA, gallic acid, propyl gallate, ascorbicacid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-test-butyl phenol, andtocopheryl;

binders (adhesives), i.e., agents that impart cohesive properties topowdered materials through particle-particle bonding, such as matrixbinders (dry starch, dry sugars), film binders (PVP, starch paste,celluloses, bentonite, sucrose), and chemical binders (polymericcellulose derivatives, such as carboxy methyl cellulose, HPC and HPMC;sugar syrups; corn syrup; water soluble polysaccharides such as acacia,tragacanth, guar and alginates; gelatin; gelatin hydrolysate; agar;sucrose; dextrose; and non-cellulosic binders, such as PVP, PEG, vinylpyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose);

bufferants, where the acid is a pharmaceutically acceptable acid, suchas hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid,adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbicacid, benzoic acid, boric acid, butyric acid, carbonic acid, citricacid, fatty acids, formic acid, fumaric acid, gluconic acid,hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid,methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid,succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid and uric acid, and where the base is apharmaceutically acceptable base, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, or a salt of a pharmaceuticallyacceptable cation and acetic acid, acrylic acid, adipic acid, alginicacid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid,boric acid, butyric acid, carbonic acid, citric acid, a fatty acid,formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalicacid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonicacid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaricacid, thioglycolic acid, toluenesulfonic acid, and uric acid;

chelating agents, such as EDTA and EDTA salts;

coagulants, such as alginates;

colorants or opaquants, such as titanium dioxide, food dyes, lakes,natural vegetable colorants, iron oxides, silicates, sulfates, magnesiumhydroxide and aluminum hydroxide;

coolants, such as halogenated hydrocarbons (e.g., trichloroethane,trichloroethylene, dichloromethane, fluorotrichloromethane),diethylether and liquid nitrogen;

cryoprotectants, such as trehelose, phosphates, citric acid, tartaricacid, gelatin, dextran and mannitol;

diluents or fillers, such as lactose, mannitol, talc, magnesiumstearate, sodium chloride, potassium chloride, citric acid, spray-driedlactose, hydrolyzed starches, directly compressible starch,microcrystalline cellulose, cellulosics, sorbitol, sucrose,sucrose-based materials, calcium sulfate, dibasic calcium phosphate anddextrose;

disintegrants or super disintegrants, such as croscarmellose sodium,starch, starch derivatives, clays, gums, cellulose, cellulose derivates,alginates, crosslinked polyvinylpyrrolidone, sodium starch glycolate andmicrocrystalline cellulose;

hydrogen bonding agents, such as magnesium oxide;

flavorants or desensitizers, such as spray-dried flavors, essential oilsand ethyl vanillin;

ion-exchange resins, such as styrene/divinyl benzene copolymers, andquaternary ammonium compounds;

plasticizers, such as polyethylene glycol, citrate esters (e.g.,triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate),acetylated monoglycerides, glycerin, triacetin, propylene glycol,phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castoroil, sorbitol and dibutyl seccate;

preservatives, such as ascorbic acid, boric acid, sorbic acid, benzoicacid, and salts thereof, parabens, phenols, benzyl alcohol, andquaternary ammonium compounds;

solvents, such as alcohols, ketones, esters, chlorinated hydrocarbonsand water;

sweeteners, including natural sweeteners such as maltose, sucrose,glucose, sorbitol, glycerin and dextrins, and artificial sweeteners,such as aspartame, saccharine and saccharine salts; and

thickeners (viscosity modifiers, thickening agents), such as sugars,polyvinylpyrrolidone, cellulosics, polymers and alginates.

Additives can also be materials such as proteins (e.g., collagen,gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates(e.g., alginates, carrageenan, cellulose derivatives, pectin, starch,chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural orsynthetic waxes; carnuaba wax; fatty acids (e.g., stearic acid,hydroxystearic acid); fatty alcohols; sugars; shellacs, such as thosebased on sugars (e.g., lactose, sucrose, dextrose) or starches;polysaccharide-based shellacs (e.g., maltodextrin and maltodextrinderivatives, dextrates, cyclodextrin and cyclodextrin derivatives);cellulosic-based shellacs (e.g., microcrystalline cellulose, sodiumcarboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose,hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate); inorganics, such asdicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc andtitania; polyols, such as mannitol, xylitol and sorbitol; polyethyleneglycol esters; and polymers, such as alginates, poly(lactidecoglycolide), gelatin, crosslinked gelatin, and agar-agar.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given additive is oftenclassified differently by different practitioners in the field, or iscommonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

6. Dosage Forms

The compositions of the present invention can be processed byagglomeration, air suspension chilling, air suspension drying, balling,coacervation, coating, comminution, compression, cryopelletization,encapsulation, extrusion, wet granulation, dry granulation,homogenization, inclusion complexation, lyophilization, melting,microencapsulation, mixing, molding, pan coating, solvent dehydration,sonication, spheronization, spray chilling, spray congealing, spraydrying, or other processes known in the art. The compositions can beprovided in the form of a minicapsule, a capsule, a tablet, an implant,a troche, a lozenge (minitablet), a temporary or permanent suspension,an ovule, a suppository, a wafer, a chewable tablet, a quick or fastdissolving tablet, an effervescent tablet, a buccal or sublingual solid,a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, atriturate, a platelet, a strip or a sachet. Compositions can also beadministered as a “dry syrup,” where the finished dosage form is placeddirectly on the tongue and swallowed or followed with a drink orbeverage. These forms are well known in the art and are packagedappropriately. The compositions can be formulated for oral, nasal,buccal, ocular, urethral, transmucosal, vaginal, topical or rectaldelivery, although oral delivery is presently preferred.

The pharmaceutical composition and/or the solid carrier particles can becoated with one or more enteric coatings, seal coatings, film coatings,barrier coatings, compress coatings, fast disintegrating coatings, orenzyme degradable coatings. Multiple coatings can be applied for desiredperformance. Further, the dosage form can be designed for immediaterelease, pulsatile release, controlled release, extended release,delayed release, targeted release, synchronized release, or targeteddelayed release. For release/absorption control, solid carriers can bemade of various component types and levels or thicknesses of coats, withor without an active ingredient. Such diverse solid carriers can beblended in a dosage form to achieve a desired performance. Thedefinitions of these terms are known to those skilled in the art. Inaddition, the dosage form release profile can be effected by a polymericmatrix composition, a coated matrix composition, a multiparticulatecomposition, a coated multiparticulate composition, an ion-exchangeresin-based composition, an osmosis-based composition, or abiodegradable polymeric composition. Without wishing to be bound bytheory, it is believed that the release may be effected throughfavorable diffusion, dissolution, erosion, ion-exchange, osmosis orcombinations thereof.

When formulated as a capsule, the capsule can be a hard or soft gelatincapsule, a starch capsule, or a cellulosic capsule. Although not limitedto capsules, such dosage forms can further be coated with, for example,a seal coating, an enteric coating, an extended release coating, or atargeted delayed release coating. These various coatings are known inthe art, but for clarity, the following brief descriptions are provided:

Seal coating, or coating with isolation layers: Thin layers of up to 20microns in thickness can be applied for variety of reasons, includingfor particle porosity reduction, to reduce dust, for chemicalprotection, to mask taste, to reduce odor, to minimize gastrointestinalirritation, etc. The isolating effect is proportional to the thicknessof the coating. Water soluble cellulose ethers are preferred for thisapplication. HPMC and ethyl cellulose in combination, or Eudragit E100,may be particularly suitable for taste masking applications. Traditionalenteric coating materials listed elsewhere can also be applied to forman isolating layer.

Extended release coating: The term “extended release coating” as usedherein means a coating designed to effect delivery over an extendedperiod of time. Preferably, the extended release coating is apH-independent coating formed of, for example, ethyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, acrylic esters, or sodium carboxymethylcellulose. Various extended release dosage forms can be readily designedby one skilled in art to achieve delivery to both the small and largeintestines, to only the small intestine, or to only the large intestine,depending upon the choice of coating materials and/or coating thickness.

Enteric coating: The term “enteric coating” as used herein relates to amixture of pharmaceutically acceptable excipients which is applied to,combined with, mixed with or otherwise added to the carrier orcomposition. The coating may be applied to a compressed or molded orextruded tablet, a gelatin capsule, and/or pellets, beads, granules orparticles of the carrier or composition. The coating may be appliedthrough an aqueous dispersion or after dissolving in appropriatesolvent. Additional additives and their levels, and selection of aprimary coating material or materials will depend on the followingproperties:

1. resistance to dissolution and disintegration in the stomach;

2. impermeability to gastric fluids and drug/carrier/enzyme while in thestomach;

3. ability to dissolve or disintegrate rapidly at the target intestinesite;

4. physical and chemical stability during storage;

5. non-toxicity;

6. easy application as a coating (substrate friendly); and

7. economical practicality.

Dosage forms of the compositions of the present invention can also beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to effect release in the lowergastrointestinal tract. The enteric coated dosage form may be acompressed or molded or extruded tablet/mold (coated or uncoated)containing granules, pellets, beads or particles of the activeingredient and/or other composition components, which are themselvescoated or uncoated. The enteric coated oral dosage form may also be acapsule (coated or uncoated) containing pellets, beads or granules ofthe solid carrier or the composition, which are themselves coated oruncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the lower intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. Thepreferred method for delay of release is coating. Any coatings should beapplied to a sufficient thickness such that the entire coating does notdissolve in the gastrointestinal fluids at pH below about 5, but doesdissolve at pH about 5 and above. It is expected that any anionicpolymer exhibiting a pH-dependent solubility profile can be used as anenteric coating in the practice of the present invention to achievedelivery to the lower gastrointestinal tract. The preferred polymers foruse in the present invention are anionic carboxylic polymers. The morepreferred polymers and compatible mixtures thereof, and some of theirproperties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media ofpH>7.

Acrylic polymers (preferred). The performance of acrylic polymers(primarily their solubility in biological fluids) can vary based on thedegree and type of substitution. Examples of suitable acrylic polymersinclude methacrylic acid copolymers and ammonia methacrylate copolymers.The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are availableas solubilized in organic solvent, aqueous dispersion, or dry powders.The Eudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for extended release. TheEudragit series E dissolve in the stomach. The Eudragit series L, L-30Dand S are insoluble in stomach and dissolve in the intestine.

Cellulose Derivatives (also preferred). Examples of suitable cellulosederivatives are ethyl cellulose; reaction mixtures of partial acetateesters of cellulose with phthalic anhydride. The performance can varybased on the degree and type of substitution. Cellulose acetatephthalate (CAP) dissolves in pH>6. Aquateric (FMC) is an aqueous basedsystem and is a spray dried CAP psuedolatex with particles<1 μm. Othercomponents in Aquateric can include pluronics, Tweens, and acetylatedmonoglycerides; cellulose acetate trimellitate (Eastman);methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulosephthalate (HPMCP). The performance can vary based on the degree and typeof substitution. HP-50, HP-55, HP-55S, HP-55F grades are suitable;hydroxypropylmethyl cellulose succinate (HPMCS; AQOAT (Shin. Etsu)). Theperformance can vary based on the degree and type of substitution.Suitable grades include AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and. AS-HG (HF), which dissolves at higherpH. These polymers are offered as granules, or as fine powders foraqueous dispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids; and

Cotteric (by Colorcon).

Combinations of the above materials can also be used.

The coating can, and usually does, contain a plasticizer and possiblyother coating excipients such as colorants, talc, and/or magnesiumstearate, which are well known in the art. Suitable plasticizersinclude: triethyl citrate (Citroflex 2), triacetin (glyceryltriacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400(polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the lower intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants,stabilizers such as hydroxypropylcellulose, acid/base may be added tothe coatings besides plasticizers to solubilize or disperse the coatingmaterial, and to improve coating performance and the coated product.

A particularly suitable methacrylic copolymer is Eudragit L®,particularly L30D® and Eudragit 100-55®, manufactured by Rohm Pharma,Germany. In Eudragit L-30 D®, the ratio of free carboxyl groups to estergroups is approximately 1:1. Further, the copolymer is known to beinsoluble in gastrointestinal fluids having pH below 5.5, generally1.5-5.5, i.e., the pH generally present in the fluid of the uppergastrointestinal tract, but readily soluble or partially soluble at pHabove 5.5, i.e., the pH generally present in the fluid of lowergastrointestinal tract.

Another methacrylic acid polymer which is suitable for use in coatingthe composition or solid carrier which can be employed in thecompositions and methods described herein, either alone or incombination with other coatings, is Eudragit S®, manufactured by RohmPharma, Germany. Eudragit S differs from Eudragit L-30-D only insofar asthe ratio of free carboxyl groups to ester groups is approximately 1:2.Eudragit S is insoluble at pH below 5.5, but unlike Eudragit L-30-D, ispoorly soluble in gastrointestinal fluids having pH of 5.5-7.0, such asis present in the small intestine media. This copolymer is soluble at pH7.0 and above, i.e., the pH generally found in the colon. Eudragit S canbe used alone as a coating to provide delivery of beginning at the largeintestine via a delayed release mechanism. In addition, Eudragit 5,being poorly soluble in intestinal fluids below pH 7, can be used incombination with Eudragit L-30-D, soluble in intestinal fluids above pH5.5, in order to effect a delayed release composition. The more EudragitL-30 D used the more proximal release and delivery begins, and the moreEudragit S used, the more distal release and delivery begins. BothEudragit L-30-D and Eudragit S can be substituted with otherpharmaceutically acceptable polymers with similar pH solubilitycharacteristics.

Preferred materials include shellac, acrylic polymers, cellulosicderivatives, polyvinyl acetate phthalate, and mixtures thereof. Morepreferred materials include Eudragit series E, L, S, RL, RS, NE, L®,L300®, S®, 100-55®, cellulose acetate phthalate, Aquateric, celluloseacetate trimellitate, ethyl cellulose, hydroxypropyl methyl cellulosephthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetatephthalate, and Cotteric. Most preferred materials include Eudragitseries L, L300, S, L100-55, cellulose acetate phthalate, Aquateric,ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.

Extended release and targeted delayed release coatings for dosage formsof the compositions of the present invention are described morecompletely in U.S. Pat. Nos. 5,622,721 and 5,686,105, the disclosures ofwhich are incorporated herein by reference in their entirety.

Fast-Disintegrating Coatings for Immediate Release: Immediate releasecoating of solid carriers is commonly used to improve product eleganceas well as for a moisture barrier, and taste and odor masking. Rapidbreakdown of the film in gastric media is important, leading toeffective disintegration and dissolution. Eudragit RD100 (Rohm) is anexample of such a coating. It is a combination of a water insolublecationic methacrylate copolymer with a water soluble cellulose ether. Inpowder form, it is readily dispensable into an easily sprayablesuspension that dries to leave a smooth film. Such films rapidlydisintegrate in aqueous media at a rate that is independent of pH andfilm thickness.

7. Processes

The compositions of the present invention can be prepared by a varietyof processes to apply an encapsulation coat onto a substrate or to forma substrate-free solid carrier such as a multiparticulate or a powder.The commonly utilized coating and pelletization processes includeballing, spheronization, extrusion, spray congealing, spray drying, pancoating, fluidized bed coating, melt extrusion, crystallization,cryopelletization, nanoencapsulation, coacervation, etc. It is alsoclear to one skilled in the art that appropriate additives can also beintroduced to the composition or during the processes to facilitate thepreparation of the solid carrier or the dosage forms, depending on theneed of the individual process.

A coating process frequently involves spraying a coating solution onto asubstrate. The coating solution can be a molten solution of theencapsulation coat composition free of a dispersing medium. The coatingsolution can also be prepared by solubilizing or suspending thecomposition of the encapsulation coat in an aqueous medium, an organicsolvent, a supercritical fluid, or a mixture thereof. At the end of thecoating process, the residual dispersing medium can be further removedto a desirable level utilizing appropriate drying processes, such asvacuum evaporation, heating, freeze drying, etc.

A pelletization process typically involves preparing a molten solutionof the composition of the solid carrier or a dispersion of thecomposition of the solid carrier solubilized or suspended in an aqueousmedium, an organic solvent, a supercritical fluid, or a mixture thereof.Such solution or dispersion is then passed through a certain opening toachieve the desired shape, size, and other properties. Similarly,appropriate drying processes can be adopted to control the level of theresidual dispersing medium, if necessary.

The processes described above, the combination of the processes, or themodification of the processes are well know in the art. Some of theprocesses are briefly described herein for reference.

Balling, Spheronization or Extrusion

In a broad sense, pellets are very much like granules and bead; thetechniques for producing pellets can also produce granules, beads, etc.Pellets, granules or beads are formed with the aid of a pelletizer,spheronizer or extruder. The pelletizer, spheronizer or extruder is ableto form approximately spherical bodies from a mass of finely dividedparticles continuously, by a rolling or tumbling action on a flat orcurved surface with the addition of a liquid.

Pelletizers can be classified based on the angle of their axis ashorizontal drum or inclined dish pelletizers. Rotary fluidizedgranulators can also be used for pelletization. A standard fluidizeddrier bowl can be replaced with a rotating plate as an air distributor.For granulation, a binder liquid is sprayed from via one or two binarynozzles located axially to the rotational movement of the powder bed.This operation results in rounding of the granules to approximatelyspherical pellets. Such balling or agitation techniques can beinfluenced by operating conditions, such as bridging/binding liquidrequirements, residence time of the material in the pelletizer, speedand angle of inclination of the pelletizer, amount of material fed tothe pelletizer, choice and levels of binder, etc. One skilled in the artcan readily adjust such factors to produce a satisfactory product.

The components of the invention can also be self binding. Liquidcomponents can be pelletized with the aid of a suitable solidifying,binding or thickening agents.

Similarly, the choice of an appropriate binder for a given applicationis readily determined by one skilled in the art. At a minimum, thebinder must be capable of wetting the surfaces of the particle beingpelletized or granulated. Binders must have sufficient wet strength toallow agglomerates to be handled, and sufficient dry strength to makethem suitable for their intended purposes. Each process, however, makesuse of a different system of forces and may require a differentagglomerate strength. The final selection of the binder should be madeon the basis of the type of equipment that is used. The size and sizedistribution of pellets, bulk density, strength and flow properties alsoaffect the performance of the pellets, and these properties can beadjusted by one skilled in the art by the inclusion of additives, choiceof equipment, and processing conditions.

Extrusion is a well-known method of applying pressure to a damp ormelted composition until it flows through an orifice or a definedopening. The extrudable length varies with the physical characteristicsof the material to be extruded, the method of extrusion, and the processof manipulation of the particles after extrusion. Various types ofextrusion devices can be employed, such as screw, sieve and basket,roll, and ram extruders.

Encapsulation by Extrusion: In this method, the lipid composition in theform of an emulsion is added to a low moisture melt of low maltodextrin,or sugar, or modified edible starch, mixed and extruded into a coldbath. The solidified composition can be further ground down. Optionally,centrifugal extrusion can be utilized for efficiency.

Melt Extrusion: Components of the invention can be melted and extrudedwith a continuous, solvent free extrusion process, with or withoutinclusion of additives. Such a process is well-established andwell-known to skilled practitioners in the art.

Spheronization

Spheronization is the process of converting material into spheres, theshape with the lowest surface area to volume ratio. Spheronizationtypically begins with damp extruded particles. The extruded particlesare broken into uniform lengths instantaneously and graduallytransformed into spherical shapes. In addition, powdered raw materials,which require addition of either liquid or material from a mixer, can beprocessed in an air-assisted spheronizer.

Spray Congealing

Spray congealing is method that is generally used in changing thestructure of the materials, to obtain free flowing powders from liquidsand to provide pellets ranging in size from about 0.25 to 2.0 mm. Spraycongealing is process in which a substance of interest is allowed tomelt, disperse, or dissolve in a hot melt of other additives, and isthen sprayed into an air chamber wherein the temperature is below themelting point of the formulation components, to provide sphericalcongealed pellets. The air removes the latent heat of fusion. Thetemperature of the cooled air used depends on the freezing point of theproduct. The particles are held together by solid bonds formed from thecongealed melts. Due to the absence of solvent evaporation in most spraycongealing processes, the particles are generally non porous and strong,and remain intact upon agitation. The characteristics of the finalcongealed product depend in part on the properties of the additivesused. The rate of feeding and inlet/outlet temperatures are adjusted toensure congealing of the atomized liquid droplet. The feed should haveadequate viscosity to ensure homogeneity. The conversion of molten feedinto powder is a single, continuous step. Proper atomization and acontrolled cooling rate are critical to obtain high surface area,uniform and homogeneous congealed pellets. Adjustment of theseparameters is readily achieved by one skilled in the art.

The spray congealing method is particularly suitable for heat labilesubstances, since ambient temperature is used to dry, and for moisturesensitive substances, since non-aqueous compositions can be utilized.Spray congealing is similar to spray drying, except that no solvent isutilized. Spray congealing is a uniform and rapid process, and iscompleted before the product comes in contact with any equipmentsurface. Most additives that are solid at room temperature and meltwithout decomposition are suitable for this method.

Conventional spray dryers operating with cool inlet air have been usedfor spray congealing. Several methods of atomization of molten mass canbe employed, such as pressure, or pneumatic or centrifugal atomization.For persons skilled in the spray congealing art, it is well known thatseveral formulation aspects, such as matrix materials, viscosity, andprocessing factors, such as temperature, atomization and cooling rateaffect the quality (morphology, particle size distribution, polymophismand dissolution characteristics) of spray congealed pellets. The spraycongealed particles may be used in tablet granulation form,encapsulation form, or can be incorporated into a liquid suspensionform.

Solvent Dehydration (Spray Drying)

For compositions that are oily in nature, the spray drying technique iscommonly employed. The oily material is commonly mixed with a polymericmaterial, such as gelatin, vegetable gum, modified starch, dextrin, orother appropriate additives. An emulsifier is added, if needed, to forman oil-in-water emulsion. The emulsion is atomized into a column ofheated air in a drying chamber, resulting in rapid evaporation of water.Alternatively, the emulsion is atomized directly into a polar solvent,such as isopropanol, ethanol, glycerol or polyglycols, to dehydrate theaerosolized particle. This method is particularly suitable forcompositions containing lipophilic actives or additives that result inlipophilic cores. Spray drying/solvent dehydration can also be appliedto hydrophilic active ingredients or additives to form an oil in wateremulsion which is spray dried. This results in a homogenous solidcomposition. Furthermore, water or organic solvent based formulationscan be spray dried by using inert process gas, such as nitrogen, argonand the like.

Crystallization

Components of the present invention can be dissolved in appropriatesolvents and subjected to spherical crystallization techniqueswell-known in the art.

Nanoencapsulation

Nanoencapsulation involves solubilizing an aqueous solution of an activeingredient and other components in a weakly polar vehicle. Micelles areformed with the active in an organic outer phase. Then, an amphiphilicmonomer is added to the lipophilic external phase. The mixed micellesthus formed are then polymerized with the aid of a suitable procedure,such as UV or gamma radiation, heat, or chemical agents. The hardenedsolidified micelles are made to undergo phase exchange by replacing anouter lipophilic vehicle by water. By selecting appropriate monomers,networking agents and auxiliary materials, nanoncapsules as small as 80to 250 nm can be prepared.

Supercritical Fluid Processes

Components of the present invention can be dispersed in a supercriticalfluid and crystallized as needed. Current techniques involvingsupercritical fluids include precipitation by rapid expansion ofsupercritical solutions, gas anti-solvent processes, and precipitationfrom gas saturated solutions.

Coacervation

Coacervation is a transfer of macromolecules with film properties from asolvated state in a coacervation phase into a phase in which there is afilm around each particle. The coacervation method involves dispersingthe composition in a dispersion of a polymeric colloid, such as gelatinalginate, and shock treating the mixture with temperature or pH, etc.,to generate a two-phase system. The desired phase is then hardened witha cross-linking agent, such as glutaraldehyde.

Cryopelletization

The cryopelletization procedure allows conversion of a molten mass,aqueous solution or suspension into solid, bead-like particles. Themolten mass solutions or suspensions are dripped by means of anappropriately designed device into liquid nitrogen. The production ofsmall drops and liquid nitrogen cooling permit very rapid and uniformfreezing of the material processed. The pellets are further dried inconventional freeze dryers. Cryopelletization can also be carried outunder aseptic conditions for sterile processing. The most critical stepproducing spherical particles by globulization is the droplet formation.Droplet formation is influenced by formulation related variables, suchas the nature of the active ingredient and additives, viscosity, totalsolid content, surface tension, etc. Extra care must be undertaken withprocessing of suspensions to ensure homogeneity. In addition, equipmentdesign and processing variable also play an important role. One skilledin the art can readily balance the various factors to produce asatisfactory product. Enteric matrix pellets can be formed that includepolyacrylic acid (e.g. Carbopol) with a high molecular weightpolyethylene (such as PEG-20,000).

Other processes suitable for producing solid compositions of thepharmaceutical compositions of the present invention include extrusionand spray chilling. These processes are described in detail in U.S. Pat.Nos. 5,965,161 and 5,539,000 respectively, the disclosures of which areincorporated herein by reference.

For processing of encapsulated compositions, various methods can beused. The term “microencapsulation” applies to enclosure or encasementin microcapsules. Microencapsulation is a means of applying coatings tosmall particles of solids or droplets of liquids and dispersions. Theterms “coated,” “protected” or “layered” are commonly usedinterchangeably with the term “encapsulated.” All of these terms can beused to refer to practically any core material that is encased orenclosed in an outer shell. Typical equipment used to apply coatingincludes a conventional pan (Pellegrini; Italy), a modified perforatedpan (multicoater, Thomas Eng., IL) or a Wurster coater in a Glatt powderdoater/granulator (Glatt Airtechniques).

Solvent Based Solution Coating

Solvent-based coating is when the components of the invention aresolubilized and/or dispersed in a solvent. The solvent can be aqueous.When the solvent is aqueous-based, the components can be emulsified withan appropriate emulsifier, organic solvent, or a supercritical fluid.Solvents with a lower melting point than water and higher evaporationnumbers are preferred. Solvent mixtures with other organic solvents orwater are often employed to get appropriate viscosity and componentsolubilization. Typical solvents include ethanol, methanol, isopropanol,acetone, dichloromethane, trichloromethane and ethyl acetate.Appropriate polymers can also be added as needed. Cellulosic derivativesand polymethacrylates are particularly suitable additives for organicsolvent coating. Dissolution and solubilization of the components isfacilitated by rigorous stirring or heating. Plasticizers may be also beadded to stimulate dissolution. Colorants and antisticking agents can beemployed as needed.

Substrate surface area, shape, porosity and stability are importantdeterminants of good coating. Spherical particles are preferred, andthese may be produced through spheronization or a sphericalcrystallization process. Crystals or compact granules from drycompaction or extrusion processes, often available commercially, serveas good substrates.

Encapsulation can be conducted by traditional pan coating or fluidizedbed techniques. Several process (air supply, temperature, spray rate,spray system, powder feed, attrition) and formulation factors determinethe quality of the end product, and one skilled in the art can readilyadjust such parameters as needed.

Air suspension in a rotary fluidized bed granulator can used to depositthe encapsulation coat on to a substrate, thus allowing a high rate ofdrug application with low drug loss. Furthermore, both aqueous andorganic solvents can be used. The Wurster process, an air suspensiontechnique, is more suitable for encapsulations involving very finepowders.

Solvent-Free Coating

This process entails using coating materials that can be applied in amolten state. The selection of proper coating materials depends onmelting point, melting point range and the viscosity in the liquidstate. A fluidized bed is ideal for molten coatings of substrates thatrange from about 100-2000 microns in size. Fluidized bed coating,spraying molten materials, involves achieving a proper balance ofprocess parameters that allow proper encapsulation to occur. Substrateparticles that are suspended and separated from each other by thefluidization air enter a zone of finely atomized coating liquid. Coatingoccurs as the liquid droplets, which are substantially smaller in sizethan substrate, impact the particles, spread, and solidify. Multiplelayers can be coated, and the completion of spraying is followed by aproduct stabilization or cooling step. Some critical success parametersinclude bed temperature, atomization, atomization fluid temperature, ordroplet size, spray type, spray rate, rate of coating dropletsolidification on particle surfaces, particle size, shape, etc. Inertmaterials such as sodium chloride, citric acid, potassium chloride canserve as substrates. One skilled in the art can readily adjust suchparameters to achieve a satisfactory product.

The processes described above are suitable for treating substrate-basedcompositions or non-substrate-based compositions of the presentinvention. Thus, in one embodiment, pharmaceutical compositions of thepresent invention do not include a seed particle, such as a conventionaldrug or other additive aggregate starch or sugar bead. Instead, thecompositions are processed, and the components are chosen, such that asolid composition is formed without the need to coat the compositiononto a substrate bead. Such compositions can be in the form of beadlets,beads, granules, pellets, etc., that have an approximately homogenousdistribution of active ingredient, surfactant, triglyceride and/oradditives. These compositions can be produced by means of balling inpelletizers or fluid bed granulators, and compaction orextrusion/spheronization. In addition, these compositions can beproduced using solvent-free spray congealing processes or dropping(globulization) methods. Dropping procedures involve conversion ofaqueous solutions or suspensions to a solid form. Congealing of theliquid droplets in cooling baths can aided by a chemical reaction (e.g.,insoluble salt or complex formation), a sol/gel transition, or byfreezing in a coolant bath of liquid nitrogen or halogenatedhydrocarbons.

8. Specific Formulations

In one embodiment, the solid pharmaceutical composition includes a solidcarrier, the solid carrier including a substrate and an encapsulationcoat on the substrate. The encapsulation coat includes at least oneionic or non-ionic hydrophilic surfactant. Optionally, the encapsulationcoat can include a pharmaceutical active ingredient, a lipophiliccomponent such as a lipophilic surfactant or a triglyceride, or both apharmaceutical active ingredient and a lipophilic component.

Prior art has used surfactants in formulating coated bead compositionsto provide a wetting function, to enable hydrophobic drugs to properlyadhere to beads and/or water-soluble binders. For example, U.S. Pat. No.4,717,569 to Harrison et al. discloses coated bead compositions ofhydrophobic steroid compounds wetted by a hydrophilic surfactant andadhered to the beads by a water-soluble binder. The steroid compound ispresent as finely divided particles, held to the beads by the binder.The present inventors have surprisingly found that proper choice ofsurfactants and other components allows compositions to be prepared witha wide variety of active ingredients. For example, while the Harrisonreference discloses the use of surfactants as wetting agents, thepresent inventors have found that surfactants at higher levels, i.e., inamounts far in excess of the amounts necessary or appropriate for awetting function, enable a pharmaceutical active ingredient to be fullyor at least partially solubilized in the encapsulation coating materialitself, rather than merely physically bound in a binder matrix. In fact,while binders can optionally be used in the compositions of the presentinvention, the higher surfactant concentrations of the presentinvention, i.e., solubilizing amounts, obviate the need for binders andrender them optional instead of necessary.

The amount of hydrophilic surfactant used in this embodiment can beadjusted so as to at least partially or fully solubilize thepharmaceutical active ingredient, with the optional lipophilicsurfactants, triglycerides and solubilizer chosen to further increasethe pharmaceutical active ingredient's solubility.

A further advantage believed to accrue from the pharmaceuticalcompositions of the present invention is that upon administration of thecomposition to a patient, the high levels of surfactants and othercomponents present in the composition facilitate the rapidsolubilization of the pharmaceutical active ingredient. Thus, while theprior art composition of Harrison contains a drug in a form whichrequires further solubilization in vivo, such as by emulsification andmicellization in the gastrointestinal tract, the active ingredient incompositions of the present invention is at least partially solubilizedin the composition itself, and is further provided with surfactants andother components in the composition to facilitate rapid dispersion(emulsification/micellization) and sustained solubilization of theactive ingredient upon administration.

It should be noted that in this embodiment, the encapsulation coat canalternatively be formulated without the active ingredient. In thisaspect, an active ingredient can be provided in the composition itselfbut not in the encapsulation coat, if desired. While not presentlypreferred, such a formulation delivers the active ingredient to thepatient along with the surfactants or other components to facilitatedispersion (emulsification/micellization), thus still providing morerapid active ingredient presentation to the absorption site.Alternatively, the active ingredient can be administered in a separatedosage form, including a conventional dosage form, prior to,concurrently with, or subsequent to administration of the presentcompositions, to achieve similar advantages.

The optional lipophilic surfactant and triglycerides can be used asdesired to further enhance solubilization of the active ingredient, orto promote dispersion (emulsification/micellization) in vivo, or topromote in vivo absorption at the absorption site.

For more hydrophilic active ingredients, the materials of theencapsulation coat provides components to promote efficient transport ofthe active ingredient across the barrier membrane to promote moreeffective absorption. For these active ingredients, it is preferable toinclude a lipophilic component in the encapsulation coat.

In another embodiment, the solid pharmaceutical composition includes asolid carrier, the solid carrier including a substrate and anencapsulation coat on the substrate. The encapsulation coat includes ahydrophilic surfactant. Optionally, the encapsulation coat can include apharmaceutical active ingredient, an ionic or non-ionic hydrophilicsurfactant, or both a pharmaceutical active ingredient and a hydrophilicsurfactant. In this embodiment, the lipophilic surfactant ortriglyceride can be present in amounts to enable at least partialsolubilization of an active ingredient in the encapsulation coat, in thecomposition, or separately administered.

In another embodiment, the solid pharmaceutical composition effectivelypresents a lipophilic component with or without an active ingredient tohelp promote absorption of a hydrophilic active.

In another embodiment, the solid pharmaceutical composition includes asolid carrier, the solid carrier including a substrate and anencapsulation coat on the substrate. The encapsulation coat includes apharmaceutical active ingredient and an ionic or nonionic hydrophilicsurfactant; a pharmaceutical active ingredient and a lipophiliccomponent such as a lipophilic surfactant or a triglyceride; or apharmaceutical active ingredient and a lipophilic component such as alipophilic surfactant or a triglyceride; or a pharmaceutical activeingredient and both a hydrophilic surfactant and a lipophilic component.

In another embodiment, the solid pharmaceutical composition includes asolid carrier, wherein the solid carrier is formed of at least twocomponents selected from the group consisting of pharmaceutical activeingredients; ionic or non-ionic hydrophilic surfactants; and lipophiliccomponents such as lipophilic surfactants and triglycerides.

In this embodiment, the solid pharmaceutical composition is formulatedwithout the need for a substrate seed particle. The active ingredient,surfactants and triglycerides in the chosen combination are processed,with appropriate excipients if necessary, to form solid carriers in theabsence of a seed substrate. Preferably, the components are chosen to atleast partially solubilize the active ingredient, as described above.

9. Methods

The present invention also provides methods of using the above-describedpharmaceutical composition. In one aspect, the present inventionprovides a method of treating a patient with an active ingredient, themethod including the steps of providing a dosage form of apharmaceutical composition as described above, including an activeingredient, and administering the dosage form to the patient. Thepatient can be an animal, preferably a mammal, and more preferably ahuman.

In another aspect, the present invention provides a method including thesteps of providing a dosage form of a pharmaceutical composition asdescribed above, providing a dosage form of a pharmaceutical activeingredient, and administering the dosage forms to the patient. Thismethod is advantageous when all or part of the active ingredient or anadditional active ingredient is to be administered to the patient in aseparate dosage form prior to, concurrently with, or subsequent toadministration of the pharmaceutical composition.

In another aspect, the present invention provides a method of improvingthe palatability and/or masking the taste of an active ingredient, byproviding the active ingredient in a pharmaceutical composition asdescribed above. Since the active ingredient is encapsulated in a lipidcoat, it will not instantaneously dissolve in the mouth, but willinstead dissolve in a region past the oral cavity, thereby substantiallyavoiding or at least reducing undesirable contact between the activeingredient and the mouth.

In another aspect of the invention, the compositions enable gastricresistance or acid degradation reduction of the active ingredient.

In another aspect of the invention, the solid carrier improves thechemical stability of the active ingredient.

In another aspect of the invention, the solid carrier protects the uppergastrointestinal tract from the adverse effects of the activeingredient.

In another aspect, the present invention provides a method of improvingthe dissolution and/or absorption of a pharmaceutical active ingredient,by administering the active ingredient in a composition as describedabove, or co-administering the active ingredient with a composition asdescribed above.

EXAMPLES Example 1 Preparation of Coated Beads

Compositions according to the present invention were prepared asfollows. The specific components used are detailed in Examples 2-5.

A spraying solution of the coating materials was prepared by dissolvingthe desired amount of the active ingredient and mixing with thehydrophilic and/or lipophilic surfactants in an organic solvent or amixture of organic solvents. The organic solvent used for the coatingsolution was a mixture of methylene chloride and isopropyl alcohol in a3:1 to 1:1 weight ratio.

Commercially available sugar beads (30/35 mesh size) were coated in aconventional coating pan having a spray gun (Campbell Hausfield, DH7500) with a nozzle diameter of 1.2 mm and an air pressure of 25 psi.The bed temperature was maintained at approximately 32° C. during thespraying process. Appropriate amounts of talc were sprinkled on thebeads during the spraying process to reduce the agglomeration of coatedbeads. When the spraying process was completed, the coated beads wereallowed to cool to room temperature. The coated beads were then driedunder vacuum to minimize residual solvent levels. The dried, coatedbeads were then sieved and collected.

Example 2 Composition I

A pharmaceutical composition was prepared according to the method ofExample 1, having a substrate particle, an active ingredient(glyburide), and a mixture of a hydrophilic surfactant (PEG-40 stearate)and a lipophilic surfactant (glycerol monolaurate). The components andtheir amounts were as follows:

Component Weight (g) % (w/w) Glyburide 1 0.8 PEG-40 stearate 33 25.2Glycerol monolaurate 17 13.0 Nonpareil seed (30/35 mesh) 80 61.1

Example 3 Composition II

A pharmaceutical composition was prepared according to the method ofExample 1, having a substrate particle, an active ingredient(progesterone), a mixture of a hydrophilic surfactant (Solulan C-24) andtwo lipophilic components (deoxycholic acid and distilledmonoglycerides). The components and their amounts were as follows:

Component Weight (g) % (w/w) Progesterone 12 8.6 Solulan C-24(Amerchol)* 32 22.9 Distilled monoglycerides 8 5.7 Deoxycholic acid 85.7 Nonpareil seed (30/35 mesh) 80 57.1 *PEG-24 cholesterol ether

Example 4 Composition III

A pharmaceutical composition was prepared according to the method ofExample 1, having a substrate particle, an active ingredient(itraconazole), a mixture of non-ionic hydrophilic surfactants(Cremophor RH-40 and PEG 150 monostearate), an ionic hydrophilicsurfactant (sodium taurocholate) and a lipophilic surfactant (glycerolmonolaurate). The components and their amounts were as follows:

Component Weight (g) % (w/w) Itraconazole 20 9.7 Cremophor RH-40 (BASF)*25 12.1 Glycerol monolaurate 10 4.8 Sodium taurocholate 5 2.4 PEG-150monostearate 27 13.0 Nonpareil seed (30/35 mesh) 120 58.0 *PEG-40hydrogenated castor oil

Example 5 Composition IV

A pharmaceutical composition was prepared according to the method ofExample 1, having a substrate particle, an active ingredient(omeprazole), a mixture of a two hydrophilic surfactants (PEG-150monostearate and PEG-40 monostearate), and a triglyceride-containinglipophilic component (Maisine 35-1). The components and their amountswere as follows:

Component Weight (g) % (w/w) Omeprazole 16 8.8 PEG-150 monostearate 50.427.8 PEG-40 monostearate 25.2 13.9 Maisine 35-1 (Gattefosse)* 8.4 4.6Magnesium carbonate 1.6 0.9 Nonpareil seed (30/35 mesh) 80 44.1*linoleic glycerides

Example 6 Seal Coating

The dried, coated beads of Example 3 were further seal coated by apolymer layer. The seal coating polymer layer was applied to theprogesterone-coated beads in a Uni-Glatt fluid bed coater.Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol toform a 5% w/w solution. This seal coating solution was sprayed onto thecoated beads with a Wurster bottom spray insert. The inlet and outletair temperature were maintained at 30 and 40° C., respectively. When thespraying process was complete, the beads were further dried by supplyingdry air at 50-55° C. for 5-15 minutes. The seal coated beads were thenallowed to cool in the apparatus by supplying dry air at 20-25° C. for5-15 minutes. The dried, seal coated beads were collected and stored ina container.

Example 7 Protective Coating

The dried, coated beads of Example 5 were further coated with aprotective polymer layer. The protective coating was applied to theomeprazole coated beads by spraying with a hydroxypropyl methylcellulose(HPMC) solution. The protective coating HPMC solution was prepared bydissolving 6 grams of HPMC in ethanol. To this solution, methylenechloride was added followed by 2 mL of triethylcitrate as a plasticizerand 1 g of talc. The HPMC solution was sprayed on the beads as describedin Example 6, and the protective coated beads were then dried andcollected.

Example 8 Enteric Coating

The dried, coated beads of Example 5 were further coated with an entericcoating layer. The enteric layer was applied to the omeprazole coatedbeads by spraying a Eudragit L100 solution. Eudragit L100 is an acrylatepolymer commercially available from Rohm Pharma. The spraying solutionwas prepared by dispersing 15 g of Eudragit L100 in 200 mL of ethanol togive a clear solution. To this solution, 4 g of triethyl citrate wasthen added as a plasticizer. 2 grams of purified talc was also added tothe solution. The solution was then sprayed onto the beads, and thebeads were dried, as described in Example 6.

Example 9 Comparative Dissolution Study I

A comparative dissolution study was performed on three forms of anactive ingredient: the glyburide coated beads of Example 2, acommercially available glyburide product (Micronase®, available fromPharmacia & Upjohn), and the pure glyburide bulk drug. The dissolutionstudy was performed using a USP dissolution type 2 apparatus. For eachof the three forms, material equivalent to 5 mg of glyburide was usedfor each triplicated dissolution run in 500 mL of isotonic pH 7.4phosphate buffer. The dissolution medium was maintained at 37° C. andconstantly stirred at a speed of 100 rpm. The dissolution media weresampled at 15, 30, 45, 60, 120 and 180 minutes. At each time point, 3 mLof the medium was sampled, and the medium was replenished with 3 mL offresh buffer. The samples were filtered through a 0.45μ filterimmediately after the sampling. The filtrates were then diluted inmethanol to an appropriate concentration for a glyburide-specific HPLCassay.

The HPLC assay was performed on a Varian 9010 system by injecting 50 μLof the sample. The sample was separated on a Phenominex C18 column byrunning a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 Mpotassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoricacid), at a flow rate of 1 mL/1 min, at ambient temperature. Glyburidewas detected by its UV absorption at 229 nm.

The results of the comparative dissolution measurement were expressed asthe percent of glyburide dissolved/released in the dissolution medium ata given time, relative to the initial total glyburide content present inthe dissolution medium (5 mg/500 mL). The results are shown in FIG. 1,with the error bars representing the standard deviation. As the Figureshows, the glyburide coated beads of the present invention showed asuperior dissolution profile in the rate, the extent, and thevariability of glyburide dissolved/released into the dissolution medium,compared to the commercial Micronase® and the pure bulk drug.

Example 10 Comparative Dissolution Study II

A comparative dissolution study was performed on three forms of anactive ingredient: the progesterone coated beads of Example 3, the sealcoated, progesterone coated beads of Example 6, and the pureprogesterone bulk drug. The dissolution study was performed using a USPdissolution type 2 apparatus. For each of the three forms, materialequivalent to 100 mg of progesterone was used for each duplicateddissolution run in 900 mL of isotonic pH 7.4 phosphate buffer containing0.5% w/v of Tween 80. The dissolution medium was maintained at 37° C.and constantly stirred at a speed of 100 rpm. The dissolution media weresampled at 30, 60, 120 and 180 minutes. At each time point, 3 mL of themedium was sampled, and the medium was replenished with 3 mL of freshbuffer/Tween solution. The samples were filtered through a 0.45μ filterimmediately after the sampling. The filtrates were then diluted inmethanol to an appropriate concentration for a progesterone-specificHPLC assay.

The HPLC assay was performed on a Varian 9010 system by injecting 50 ofthe sample. The sample was separated on a Phenominex C18 column byrunning a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 Mpotassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoricacid), at a flow rate of 1 mL/min, at ambient temperature. Glyburide wasdetected by its UV absorption at 229 nm.

The results of the comparative dissolution measurement were expressed asthe percent of progesterone dissolved/released in the dissolution mediumat a given time, relative to the initial total progesterone contentpresent in the dissolution medium (100 mg/900 mL). The results are shownin FIG. 2A. As the Figure shows, the progesterone coated beads of thepresent invention, with or without a seal coating, showed superiordissolution profiles in both the rate and the extent of progesteronedissolved/released into the dissolution medium, compared to the purebulk drug.

Example 11 Comparative Dissolution Study III

A comparative dissolution study was performed on three forms of anactive ingredient: the progesterone coated beads of Example 3, the sealcoated, progesterone coated beads of Example 6, and the pureprogesterone bulk drug. Prometrium® is a capsule dosage form in whichmicronized progesterone is suspended in a blend of vegetable oils. Thedissolution of the Prometrium® capsule was performed using a USPdissolution type 1 apparatus, and the dissolution of the other sampleswas performed using a USP dissolution type 2 apparatus. For each of thethree forms, material equivalent to 100 mg of progesterone was used foreach dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer. Thedissolution medium was maintained at 37° C. and constantly stirred at aspeed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60and 180 minutes. At each time point, 3 mL of the medium was sampled, andthe medium was replenished with 3 mL of flesh buffer/Tween solution. Thesamples were filtered through a 0.45μ filter immediately after thesampling. The filtrates were then diluted in methanol to an appropriateconcentration for a progesterone-specific HPLC assay.

The HPLC assay was performed on a Varian 9010 system by injecting 50 μLof the sample. The sample was separated on a Phenominex C18 column byrunning a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 Mpotassium dihydrogen phosphate, pH adjusted to 15 using phosphoricacid), at a flow rate of 1 mL/mm, at ambient temperature. Glyburide wasdetected by its UV absorption at 229 nm.

The results of the comparative dissolution measurement were expressed asthe percent of progesterone dissolved/released in the dissolution mediumat a given time, relative to the initial total progesterone contentpresent in the dissolution medium (100 mg/900 mL. The results are shownin FIG. 2B. As the Figure shows, the progesterone coated beads of thepresent invention, with or without a seal coating, showed superiordissolution profiles in both the rate and the extent of progesteronedissolved/released into the dissolution medium, compared to thecommercial Prometrium® and the pure bulk drug.

Example 12 Comparative Dissolution Study IV

A comparative dissolution study was performed comparing the rate andextent of dissolution of the protective coated, omeprazole coated beadsof Example 7, the enteric coated, omeprazole coated beads of Example 8and a commercially available omeprazole product (Prilosec®, availablefrom Astra Zeneca). The dissolution study was performed using a USPdissolution type 2 apparatus. For each of the three dosage forms,material equivalent to 5 mg of omeprazole was used for each dissolutionrun in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolutionmedium was maintained at 37° C. and constantly stirred at a speed of 100rpm. The dissolution media were sampled at 15, 30, 45 and 60 minutes. Ateach time point, 3 mL of the medium was sampled, and the medium wasreplenished with 3 mL of fresh buffer. The samples were filtered througha 0.45μ filter immediately after the sampling. The filtrates were thendiluted in methanol to an appropriate concentration for anomeprazole-specific HPLC assay.

The HPLC assay was performed on a Varian 9010 system by injecting 50 μLof the sample. The sample was separated on a Phenominex C18 column byrunning a mobile phase of 30:70 v/v acetonitrile/phosphate buffer (pH7.4), at a flow rate of 1.1 mL/min, at ambient temperature. Omeprazolewas detected by its UV absorption at 302 nm.

The results of the comparative dissolution measurement were expressed asthe percent of omeprazole dissolved in the dissolution medium at a giventime, relative to the initial total omeprazole content present in thedissolution medium (5 mg/500 mL). The results are shown in FIG. 3. Asthe Figure shows, the omeprazole coated beads of the present inventionshowed superior dissolution profiles in both the rate and the extent ofomeprazole dissolved/released into the dissolution medium, compared tothe commercial Prilose® product.

The following non-limiting Examples 13-28 illustrate compositions thatcan be prepared according to the present invention. It should beappreciated that the compositions can be prepared in the absence of theactive ingredients and appropriate amounts of the active ingredients inany given dosage form then can be administered together or separatelywith the composition. It should also be appreciated that thecompositions can further include additional additives, excipients, andother components for the purpose of facilitating the processes involvingthe preparation of the composition or the pharmaceutical dosage form, asdescribed herein, as is well-known to those skilled in the art.

Example 13

Component Amount (g) Atorvastatin 4 Partially hydrogenated soybean oil10 Myrj 52 (PEG-40 stearate) 70 Monomuls 90-45 (glyceryl monolaurate) 20Nonpareil seed (25/30 mesh) 120

Example 14

Component Amount (g) Alendronate sodium 50 Cremophor RH-40 (PEG-40hydrogenated castor oil) 100 Capmul MCM (glyceryl caprylate/caprate) 50Sodium alginate 2 Water 5 Nonpareil seed (25/30 mesh) 200

Example 15

Component Amount (g) Ganciclovir 100 Tocopheryl PEG-1000 succinate 200Imwitor 191 (glyceryl monostearate) 30 Water 20 Nonpareil seed (25/30mesh) 400

Example 16

Component Amount (g) Simvastatin 20 Hydrogenated castor oil 40 CrodetO40 (PEG-40 oleate) 200

Example 17

Component Amount (g) Zafirlukast 7 PEG-150 monostearate 50 PEG-40monostearate 80 Peceol (glyceryl monooleate) 15

Example 18

Component Amount Salmon calcitonin 300,000 IU PEG-40 monostearate 200 gGlycerol monolaurate 100 g Water 5 g

Example 19

Component Amount (g) Lovastatin 20 Coenzyme Q10 50 PEG-40 stearate 150Glycerol monolaurate 50 Nonpareil seed (25/30 mesh) 200

Example 20

Component Amount (g) Tacrolimus 5 Solulan C-24 130 Distilledmonoglycerides 40 Deoxycholic acid 80 Nonpareil seed (35/40 mesh) 250

Example 21

Component Amount (g) Rapamycin 20 PEG-40 stearate 150 PEG-150 stearate50 Miglyol 812 20

Example 22

Component Amount (g) Pioglitazone 15 Pureco 76 20 Lutrol OP 2000 30PEG-100 hydrogenated castor oil 100 PEG-100 oleate (Crodet O-100) 100Nonpareil seed (25/30 mesh) 200

Example 23

Component Amount (g) Oxaprozin 50 Safflower oil 25 PEG-10 soya sterol(Nikkol BYS-20) 25 Myrj 52 150 Nonpareil seed (25/30 mesh) 300

Example 24

Component Amount (g) Tretinoin 50 Capmul GMO-K 50 Sodium taurocholate100 DPPC 50 DMPC 50

Example 25

Component Amount (g) Celecoxib 50 Myrj 52 100 Glycerol monolaurate 30Hydrogenated coconut oil 20 Nonpareil seed (25/30 mesh) 200

Example 26

Component Amount (g) Rofecoxib 10 Kessco PEG 1540 MS (PEG-32 stearate)160 Imwitor 312 20 Hydrogenated palm oil (Softisan 154) 20

Example 27

Component Amount (g) Fenofibrate 100 Imwitor 742 40 Imwitor 988 40Sodium alginate 4 Crodet O-40 120 Myrj 51 120 Water 20

Example 28

Component Amount (g) Saquinavir 200 HPMC 50 Myrj 52 130 Arlacel 186 20

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed and desired to be secured by United States LettersPatent is: 1-20. (canceled)
 21. A pharmaceutical composition formulatedfor oral delivery, the composition comprising: (1) an active ingredient,which is testosterone undecanoate; (2) a lipophilic surfactant, which isa mono- and/or di-glyceride; (3) a non-ionic hydrophilic surfactant,which is polyoxyl 40 castor oil (CREMPOPHOR® RH40); and (4) polyethyleneglycol; wherein the composition is free of ethanol.
 22. Thepharmaceutical composition of claim 21, wherein the mono- and/ordi-glyceride is glycerol monolinoleate (Maisine).